The objective of this review is to describe the current status of several intravaginal anti-HIV microbicidal delivery systems these delivery systems and microbicidal compounds in the context of their stage within clinical trials and their potential cervicovaginal defence successes. The global Human Immuno-Deficiency Virus (HIV) pandemic continues to spread at a rate of more than 15,000 new infections daily and sexually transmitted infections (STIs) can predispose people to acquiring HIV infection. Male-to-female transmission is eight times more likely to occur than female-to-male transmission due to the anatomical structure of the vagina as well as socio-economic factors and the disempowerment of women that renders them unable to refuse unsafe sexual practices in some communities. The increased incidence of HIV in women has identified the urgent need for efficacious and safe intravaginal delivery of anti-HIV agents that can be used and controlled by women. To meet this challenge, several intravaginal anti-HIV microbicidal delivery systems are in the process of been developed. The outcomes of three main categories are discussed in this review: namely, dual-function polymeric systems, non-polymeric systems and nanotechnology-based systems. These delivery systems include formulations that modify the genital environment (e.g. polyacrylic acid gels and lactobacillus gels), surfactants (e.g. sodium lauryl sulfate), polyanionic therapeutic polymers (e.g. carageenan and carbomer/lactic acid gels), proteins (e.g. cyanovirin-N, monoclonal antibodies and thromspondin-1 peptides), protease inhibitors and other molecules (e.g. dendrimer based-gels and the molecular condom). Intravaginal microbicide delivery systems are providing a new option for preventing the transmission of STIs and HIV.

The purpose of this research was to preliminary assess the suitability of a new method for the preparation of a solid formulation in form of powder composed by β-cyclodextrin and the supercritical extract of Rosa canina hips. The method implies the extraction of carotenoids, in particular β-carotene, from freeze dried fruits of R. canina with supercritical CO₂ at 70 °C and 300 bar, in the presence of varying quantity of ethanol as entrainer. The obtained supercritical solution is then expanded at ambient conditions into an aqueous solution of β-cyclodextrin to favour the interaction between β-cyclodextrin and the lipophilic components of the extract. β-carotene solubility (mole fraction) in supercritical CO₂ or in supercritical CO₂/ethanol mixtures were in the order of 1 10⁻⁷. The β-carotene extracted from R. canina fruits (nearly 10 μg/g of dry matrix), interacts almost quantitatively with β-cyclodextrin affording a solid phase, which presents a low apparent solubility in water. Finally the interaction with β-cyclodextrin results in a higher concentration of the β-carotene trans- form relative to the cis- form in the extracted product when collected in an aqueous solution of β-cyclodextrin with respect to the extract in n-hexane.

The main issue in the development of transdermal patches made of poly(ethyl acrylate, methyl methacrylate) (Eudragit® NE 40D, PMM) is the shrinkage phenomenon during the spreading of the latex onto the release liner. To solve this problem, the latex is usually freeze-dried and then re-dissolved in an organic solvent (method 1). To simplify the production process, we prepared an adhesive matrix by adding to the commercial PMM latex a plasticizer and an additive (anti-shrinkage agent) that avoids the shrinkage of the water dispersion spread onto the release liner (method 2). In some cases the active ingredient itself, such as potassium diclofenac (DK) and nicotine (NT), works as anti-shrinkage agent. In this work, the effects of the preparation method, types and concentrations of the plasticizer (triacetin and tributyl citrate) on the adhesive properties of the transdermal patches were investigated. The adhesive properties of the prepared patch were determined by texture analysis, peel adhesion test and shear adhesion. The PMM/plasticizer interactions were evaluated by ATR-FTIR spectroscopy. Furthermore, the in vitro skin permeation profiles of DK and NT released from the patch were determined by Franz cell method. Generally speaking, the variables that mainly modify the adhesive properties are the concentration and type of the plasticizer. The skin permeation profiles of DK and NT from the patch prepared by method 2 overlapped with those obtained with the commercial products. The results underline that the PMM latex can be used conveniently in the development of transdermal patches.

The objective of this investigation was to develop lorazepam (LZM) microemulsions as an alternative to the conventional cosolvent based formulation. Solubility of LZM in various oils and Tween 80 was determined. The ternary diagram was plotted to identify area of microemulsion existence and a suitable composition was identified to achieve desired LZM concentration. The LZM microemulsions were evaluated for compatibility with parenteral fluids, globule size, in vitro hemolysis and stability of LZM. Capmul MCM demonstrated highest solubilizing potential for LZM and was used as an oily phase. LZM microemulsions were compatible with parenteral dilution fluids and exhibited mean globule size less than 200 nm. The in vitro hemolysis studies indicated that microemulsions were well tolerated by erythrocytes. The LZM microemulsions containing amino acids exhibited good physical and chemical stability when subjected to refrigeration for 6 months.

The purpose of this article is to catalogue in a systematic way the available information about factors that may influence the outcome and variability of cascade impactor (CI) measurements of pharmaceutical aerosols for inhalation, such as those obtained from metered dose inhalers (MDIs), dry powder inhalers (DPIs) or products for nebulization; and to suggest ways to minimize the influence of such factors. To accomplish this task, the authors constructed a cause-and-effect Ishikawa diagram for a CI measurement and considered the influence of each root cause based on industry experience and thorough literature review. The results illustrate the intricate network of underlying causes of CI variability, with the potential for several multi-way statistical interactions. It was also found that significantly more quantitative information exists about impactor-related causes than about operator-derived influences, the contribution of drug assay methodology and product-related causes, suggesting a need for further research in those areas. The understanding and awareness of all these factors should aid in the development of optimized CI methods and appropriate quality control measures for aerodynamic particle size distribution (APSD) of pharmaceutical aerosols, in line with the current regulatory initiatives involving quality-by-design (QbD).

The purpose of this research was to evaluate the relation between preferential direction of pores and mechanical strength of cubic starch compacts. The preferential pore direction was quantified in SEM images of cross sections of starch compacts using a previously described algorithm for determination of the quotient of transitions (Q). This parameter and the mechanical strength were evaluated in compacts of different porosities. Starch was chosen as a model compound for materials with ductile behaviour of which tablets with low porosities can be made and which shows some elastic recovery after compaction. At medium and high porosity Q was significantly higher in the images providing a side view of the compact than in the images providing a top view (0.973 vs. 0.927 and 0.958 vs. 0.874 at 0 mm from the side of the compact and 0.956 vs. 0.854 and 0.951 vs. 0.862 at 3.5 mm), indicating that the pores were mainly oriented in the direction perpendicular to the direction of compression. This was accompanied by a lower crushing force in this direction. This could be explained by considering the pores as cracks which propagate through the sample during crushing. For both directions the crushing force decreased with increasing porosity. The yield strength of the compacts also decreased with increasing porosity, but this parameter was not dependent on the direction of crushing when the porosity was below 10%. The results show that pore direction significantly influences the crushing force but does not influence the yield strength, at porosities below 10%.

The aim of this study was to design and evaluate of mucoadhesive gel formulations for the vaginal application of clomiphene citrate (CLM) for local treatment of human papilloma virus (HPV) infections. Chitosan (CHI) and polycarbophil (PC) were covalently modified using the thioglycolic acid and L-cysteine, respectively. The formation of thiol conjugates of chitosan (CHI-TG) and polycarbophil (PC-CYS) were confirmed by FT-IR analysis and PC-CYS and CHI-TG were found to have 148.42 ± 4.16 and 41.17 ± 2.34 μmol of thiol groups per gram of polymer, respectively. One percent CLM gels were prepared by combination of various concentrations of PC and CHI with thiolated conjugates of these polymers. Hardness, compressibility, elasticity, adhesiveness and cohesiveness of the gels were measured by Texture profile analysis and the vaginal mucoadhesion was investigated by mucoadhesion test. The increasing in the amount of the thiol conjugates was found to enhance the elasticity, cohesiveness, adhesiveness and mucoadhesion of the gel formulations but not their hardness and compressibility when compared to gels prepared using their respective parent formulations. Slower release rate of CLM from gels was achieved when the polymer concentrations were increased in the gel formulations. PC and its thiol conjugate were found to prolong the release of CLM longer than 70 h unlike gel formulations prepared using CHI and its thiol conjugate which were able to release CLM up to 12 h. Stability of CLM was preserved during the 3 month stability analysis under controlled room temperature and accelerated conditions.

The purpose of this study was to develop a once daily sustained release tablet of aceclofenac using chitosan and an enteric coating polymer (hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate). Overall sustained release for 24 h was achieved by preparing a double-layer tablet in which the immediate release layer was formulated for a prompt release of the drug and the sustained release layer was designed to achieve a prolonged release of drug. The preformulation studies like IR spectroscopic and differential scanning calorimetry showed the absence of drug–excipient interactions. The tablets were found within the permissible limits for various physicochemical parameters. Scanning electron microscopy was used to visualize the surface morphology of the tablets and to confirm drug release mechanisms. Good equivalence in the drug release profile was observed when drug release pattern of the tablet containing chitosan and hydroxypropyl methylcellulose phthalate (M-7) was compared with that of marketed tablet. The optimized tablets were stable at accelerated storage conditions for 6 months with respect to drug content and physical appearance. The results of pharmacokinetic studies in human volunteers showed that the optimized tablet (M-7) exhibited no difference in the in vivo drug release in comparison with marketed tablet. No significant difference between the values of pharmacokinetic parameters of M-7 and marketed tablets was observed (p > 0.05; 95% confidence intervals). However the clinical studies in large scale and, long term and extensive stability studies at different conditions are required to confirm these results.

The purpose of this study was to design a ‘Traveller Friendly Drug Delivery System’ for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit^® E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone^®-XL, Primojel^® and ion-exchanger Tulsion^®339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan^®; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 ± 2°C/60 ± 5% RH, and 40 ± 2°C/75 ± 5%RH for 3 months showed no significant changes in the tablets quality at 30 ± 2°C/60 ± 5% RH. However, at 40 ± 2°C/75 ± 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit^® E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.

The present investigation was undertaken with the objective of formulating TC containing fast dissolving films for local delivery to oral cavity. Various film forming agents, film modifiers and polyhydric alcohols were evaluated for optimizing the composition of fast dissolving films. The potential of poloxamer 407 and hydroxypropyl-β- cyclodextrin (HPBCD) to improve solubility of TC was investigated. Fast dissolving films containing hydroxypropyl methylcellulose (HPMC), xanthan gum, and xylitol were formulated. Use of poloxamer 407 and HPBCD resulted in significant improvement in the solubility of TC. Fast dissolving films containing TC-HPBCD complex and TC-Poloxamer 407 were formulated and were evaluated for the in vitro dissolution profile and in vitro microbiological assay. Films containing TC-Poloxamer 407 exhibited better in vitro dissolution profile and in vitro antimicrobial activity as compared to the films containing TC-HPBCD complex. Effect of incorporation of eugenol on the in vivo performance of TC-Poloxamer 407 containing films was evaluated in human volunteers. Eugenol containing films improved the acceptability of TC-Poloxamer 407 films with respect to taste masking and mouth freshening without compromising the in vivo dissolution time.

To evaluate the effects of different gamma irradiation doses on PEGd,lPLA and PEG-PLGA multiblock copolymers. The behaviour of the multiblock copolymers to irradiation was compared to that of PLA, PLGA polymers. PEGd,lPLA, PEG-PLGA, PLA and PLGA polymers were irradiated by using a ⁶⁰Co irradiation source at 5, 15, 25 and 50 kGy total dose. Characterization was performed on all samples before and after irradiation, by nuclear magnetic resonance (NMR), infrared absorption spectrophotometry (FTIR) and gel permeation chromatography (GPC). The effect of gamma irradiation on polymer stability was also evaluated. Results of NMR and FTIR suggest an increase in -OH and -COOH groups, attributed to scission reactions induced by irradiation treatment. Data of GPC analysis showed that the weight average molecular weight (Mw) of polymer samples decreased with increasing irradiation dose. The extent of Mw degradation expressed as percentage of Mw reduction was more prominent for polymers with high molecular weight as PEGd,lPLA and PLA. The dominant effect of gamma-irradiation on both polymer samples was chain scission. The multiblock copolymer PEGd,lPLA presented higher sensitivity to irradiation treatment with respect to PLA, likely due to the presence of PEG in the matrix. The effect of gamma irradiation continues over a much longer period of time after gamma irradiation has been performed. It is suggested that the material reacts with oxygen to form peroxyl free radicals, which may further undergo degradation reactions during storage after irradiation.

The objective of the present research was to investigate the feasibility of using non-ionic surfactant vesicles (niosomes) as carriers for the ophthalmic controlled delivery of a water soluble local antibiotic; gentamicin sulphate. Niosomal formulations were prepared using various surfactants (Tween 60, Tween 80 or Brij 35), in the presence of cholesterol and a negative charge inducer dicetyl phosphate (DCP) in different molar ratios and by employing a thin film hydration technique. The ability of these vesicles to entrap the studied drug was evaluated by determining the entrapment efficiency %EE after centrifugation and separation of the formed vesicles. Photomicroscopy and transmission electron microscopy as well as particle size analysis were used to study the formation, morphology and size of the drug loaded niosomes. Results showed a substantial change in the release rate and an alteration in the %EE of gentamicin sulphate from niosomal formulations upon varying type of surfactant, cholesterol content and presence or absence of DCP. In-vitro drug release results confirmed that niosomal formulations have exhibited a high retention of gentamicin sulphate inside the vesicles such that their in vitro release was slower compared to the drug solution. A preparation with 1:1:0.1 molar ratio of Tween 60, cholesterol and DCP gave the most advantageous entrapment (92.02% ± 1.43) and release results (Q_8h = 66.29% ± 1.33) as compared to other compositions. Ocular irritancy test performed on albino rabbits, showed no sign of irritation for all tested niosomal formulations.

The purpose of this research was to investigate the effects of particle size on the wet massing behavior of microcrystalline cellulose (MCC). In this study, a series of six fractionated MCC grades were customized and specially classified to yield different particle size varieties of the standard grade, Comprecel M101. All seven MCC grades were extensively characterized for the physical properties and wet massing behavior using mixer torque rheometry. Effects of MCC physical properties on the maximum torque (Torque_max) were determined using partial least squares (PLS) analysis. Most physical properties varied systematically with particle size and morphological changes. Marked differences were observed in the small pore volumes (V_highP) and BET surface areas of the MCC grades. Variables that exerted dominant influences on Torque_max were identified. In particular, the significance of V_highP in governing wet mass consistency was established. The role of V_highP has not been reported in any study because this small but significant variation is likely to be obliterated or compensated by variation in other physical properties from MCC grades from different suppliers. The findings demonstrated the role of small pores in governing the wet mass consistency of MCC and provide a better understanding of MCC’s superior performance as a spheronization aid by the ability to fulfill the function as a molecular sponge to facilitate pellet formation during wet granulation processes.

The purpose of the present study was to develop and design pectin and polyvinyl pyrrolidone (PVP) blended hydrogel membranes (PEVP), with different pectin: PVP ratios (1:0.2, 1:0.4, 1:0.6, 1:0.8 and 1:1 w/w), which were prepared by using a conventional solution casting technique. An attempt has been made to characterize the hydrogel membranes by various instrumental techniques like, FTIR (Fourier transform infrared) spectroscopy, X-ray diffraction (XRD), Differential scanning calorimetry (DSC), tensile strength test and scanning electron microscopy (SEM). The release patterns of the drug (salicylic acid) from the hydrogel membrane were done in three different release mediums (pH 1.4, pH 7.4 and distilled water) and samples were analyzed spectrophotometrically at 294 nm wavelength on a UV Vis spectrophotometer. MTT assay was done to ensure cytocompatibility of the pectin/PVP hydrogel membranes using B16 melanoma cells. FTIR spectroscopy indicated the presence of secondary amide (I) absorption bands. The XRD study shows decrease in crystallinity of the hydrogel membranes with increase in PVP ratio. DSC study shows an increase in T_g of pectin after blending with PVP. It was found that tensile strength increases with increasing PVP ratios in the hydrogel membranes. The prepared hydrogel membranes were found to be biocompatible with B16 melanoma cells.

The aim of the study is to examine thermal behavior of water within reticulated structure of bacterial cellulose (BC) films by sub-ambient differential scanning calorimetry (DSC). BC films with different carbon source, either manitol (BC (a)) or glycerol (BC (b)), were produced by Acetobacter xylinum using Hestrin and Shramm culture medium under static condition at 30 ± 0.2°C for 3 days. BC samples were characterized by electron scanning microscopy and X-ray diffraction spectroscopy. The pore analysis was done by B.H.J. nitrogen adsorption. The pre-treated with 100% relative humidity, at 30.0 ± 0.2°C for 7 days samples were subjected to a between 25 and −150°C-cooling–heating cycle of DSC at 5.00°C/min rate. The pre-treated samples were also hydrated by adding 1 μl of water and thermally run with identical conditions. It is observed that cellulose fibrils of BC (a) were thinner and reticulated to form slightly smaller porosity than those of BC (b). They exhibited slightly but non-significantly different crystalline features. The freezable bound water behaved as a water confinement within pores rather than a solvent of polymer which is possible to use thermoporosimetry based on Gibb–Thomson equation to approach pore structure of BC. In comparison with nitrogen adsorption, it was found that thermoporosimetry underestimated the BC porosity, i.e., the mean diameters of 23.0 nm vs. 27.8 nm and 27.9 nm vs. 33.9 nm for BC (a) and BC (b), respectively, by thermoporosimetry vs. B.H.J. nitrogen adsorption. It may be due to large non-freezable water fraction interacting with cellulose, and the validity of pore range based on thermodynamic assumptions of Gibb–Thomson theory.

The aim of this study was to formulate extended release compression coated core tablets of fenoterol hydrobromide, a selective β₂ adrenergic receptor agonist, in an attempt to prevent nocturnal asthma. Two hydrophilic polymers viz Kollidon® SR, Polyox® WSR 303 and a hydrophobic one (Precirol® ATO5) were employed. Compression coated tablets were formulated by preparing a core tablet containing 7.5 mg drug and various amounts of polymer and Emcompress® then compressed coated with the same polymeric materials. For comparison purpose different matrix tablets were also prepared employing the same polymers. In-vitro release studies were carried out at different pH (1.2 and 6.8). Pharmacokinetics of extended release tablets as well as commercially available immediate release tablets (Berotec®) were studied after oral administration to beagle dogs using a new developed LC-MS/MS method with a lower limit of quantification of 1 ng/ml. Fenoterol release from compression coated tablets was significantly lower than matrix tablets. The mechanism of release was changed with the nature and content of polymer. The release pattern of drug from F16 containing 40 mg Kollidon® SR divided in the core tablet (15 mg) and the rest in the compressed coat (25 mg) showed a typical zero order release kinetic that could extend drug release >10 h and reasonable time for 75% to be released (t₇₅) (8.92 h). When compared to immediate release Berotec® tablet the MRT was significantly extended from 7.03 ± 0.76 to 10.93 ± 1.25 h (P < 0.001) and HVD_{t 50%Cmax} was also significantly extended from 2.71 ± 0.68 to 6.81 ± 0.67 h with expected prevention of nocturnal asthma.

The purpose of this research is to gain a greater insight into the hydrate formation processes of different carbamazepine (CBZ) anhydrate forms in aqueous suspension, where principal component analysis (PCA) was applied for data analysis. The capability of PCA to visualize and to reveal simplified structures that often underlie large data sets are explored. Different CBZ polymorphs were dispersed separately in aqueous solution, and then recovered and measured by FT-Raman spectroscopy. PCA was employed for visualizing the dynamics of the phase transformation from each CBZ polymorph to the dihydrate (DH). As a comparison to PCA visualization, the transformation process of each CBZ polymorph was quantified using PLS modeling. The results demonstrated that PCA has advantages in presenting the original data in terms of the differences and similarities, and also directly identify the statistical patterns in the data even when the data set is large. These advantages provided greater insight into the measured Raman spectra as well as the phase transformation process of CBZ polymorphs to the DH in aqueous environment.

The main aim of the present study was to evaluate potential of ternary complexation (comprising of drug, cyclodextrin and polymer) as an approach for taste masking. For this purpose famotidine with property of bitter taste was selected as a model drug. Improvement in taste masking capability of cyclodextrin towards famotidine was evaluated by formulating a ternary complex including hydrophilic polymer hydroxyl propyl methyl cellulose (HPMC 5 cps) as the third component. Phase solubility analysis at 25 °C was carried out for both the binary systems (viz. drug–cyclodextrin and drug–polymer) and the ternary system (drug–cyclodextrin–polymer). Ternary complex was prepared using solution method and was further characterized using XRD, DSC, FT-IR and microscopic studies. In vitro dissolution study was carried out to see the effect of ternary complexation on drug release. Taste perception study was carried out on human volunteers to evaluate the taste masking ability of ternary complexation. Results obtained from phase solubility analysis showed that the combined use of polymer and cyclodextrin effectively increased the stability constant of the complex [from 538 M⁻¹ for binary system to 15,096 M⁻¹ for ternary system]. Ternary system showed effective taste masking as compared to binary complex and at the same time showed no limiting effect on the drug release (D.E_15min = 90%). The effective taste masking was attributed to the enhanced complexation of famotidine in ternary system compared to binary system and the same was confirmed from the characterization studies. In conclusion, the study confirmed that ternary complexation can be utilized as an alternative approach for effective taste masking.

The purpose of this research was the preparation of four formulations containing hydrocortisone acetate (HCA) for topical application, including two aqueous systems (hydrophilic microemulsion and aqueous gel) and two systems with dominant hydrophobicity (hydrophobic microemulsion and ointment). The formulations were tested for the release and permeation of HCA across an animal membrane. The release of HCA was found comparable for the four systems. The two microemulsions promote permeation across an ex-vivo membrane, examined by means of a Franz cell. Hydrophobic microemulsion guarantees the highest solubility (2,370 μg/ml) and flux (133 μg/cm².h) of the drug, since it contains almost 40% Transcutol, a permeation enhancer. Gel and ointment provide lower solubility and flux, being the values, related to the ointment, the lowest ones (562 μg/ml and 0.4 μg/cm².h). Experimental results allow the conclusion that gel and ointment can be suitable when it is desirable to minimize absorption of topically applied HCA as to keep the drug restricted to the diseased area and prevent side effects of the systemic presence of HCA.

Preformulation studies were performed on a hemiglutarate ester prodrug of Δ⁹-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T_g close to 0°C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170°C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at −18°C but demonstrated higher degradation at 4°C, 25°C and 40°C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

The aim of the present study was to enhance the dissolution rate of gliclazide using its solid dispersions (SDs) with polyethylene glycol (PEG) 6000. The phase solubility behavior of gliclazide in presence of various concentrations of PEG 6000 in 0.1 N HCl was obtained at 37 °C. The solubility of gliclazide increased with increasing amount of PEG 6000 in water. Gibbs free energy ( $$\Delta G_{{\text{tr}}}^{\text{o}} $$ ) values were all negative, indicating the spontaneous nature of gliclazide solubilization and they decreased with increase in the PEG 6000 concentration, demonstrating that the reaction conditions became more favorable as the concentration of PEG 6000 increased. The SDs of gliclazide with PEG 6000 were prepared at 1:1, 1:2 and 1:5 (gliclazide/PEG 6000) ratio by melting-solvent method and solvent evaporation method. Evaluation of the properties of the SDs was performed by using dissolution, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The SDs of gliclazide with PEG 6000 exhibited enhanced dissolution rate of gliclazide, and the rate increased with increasing concentration of PEG 6000 in SDs. Mean dissolution time (MDT)of gliclazide decreased significantly after preparation of SDs and physical mixture with PEG 6000. The FTIR spectroscopic studies showed the stability of gliclazide and absence of well-defined gliclazide–PEG 6000 interaction. The DSC and XRD studies indicated the microcrystalline or amorphous state of gliclazide in SDs of gliclazide with PEG 6000.

It has recently been highlighted that the release behavior of pellets containing microcystalline cellulose (MCC) as the spheronizing agent may be impaired by the lack of disintegration. Although alternative spheronizing excipients have been proposed, their overall advantages have not thoroughly been assessed. In the present work, the possible use of β-cyclodextrin (βCD) was therefore explored for the manufacturing of pellets with a potential for effective disintegration and immediate release of poorly soluble active ingredients. MCC/βCD powder formulations containing no drug or model drugs with different water solubility, able to form inclusion compounds with the employed cyclodextrin, were pelletized by agglomeration in rotary fluid bed equipment. By applying successive statistical experimental designs, the most critical formulation and operating parameters were identified and optimal manufacturing processes were ultimately set up. High yields of pellets provided with satisfactory physical-technological characteristics were obtained using powder formulations with up to 80% βCD. Based on dissolution testing results, the suitability of βCD for the preparation of disintegrating MCC-containing pellets with improved dissolution performance was finally demonstrated.

The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is found to be a more efficient solubilizer for all the drugs studied. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model is used to estimate the drug solubility in NMP–water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that it’s strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log K_ow of the drugs and the cosolvency coefficients. The correlation between log K_ow and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes.

This study examined the release of carbamazepine (CBZ) from hydrophobic (Compritol® 888 ATO) and hydrophilic-hydrophobic matrix combination (Compritol® 888 ATO-hydroxpropyl methylcellulose, HPMC). Hydrophobic matrix tablets were prepared by hot fusion technique, while hydrophilic-hydrophobic matrix tablets were prepared by wet granulation technique. The properties of the compressed matrix tablets were determined according to the US Pharmacopoeia. Both matrix formulations displayed a controlled-release profile when compared to the reference formulation (Tegretol® CR 200). The bioavailability of CBZ formulations and Tegretol® CR 200 were evaluated in beagle dogs. Carbamazepine presented a significant higher bioavailability from matrix tablets containing hydrophilic polymer (HPMC) than that obtained from Tegretol® CR200. The average inter-subject plasma concentration variability CV% was the least with tablet containing hydrophilic polymer (HPMC) and was the highest with Tegretol® CR 200 (33.8 and 54.1, respectively). Analysis of variance applied to log $${\text{AUC}}_{0 - \alpha } $$ and log C _max showed statistical significant differences among the three formulations (P < 0.05). Plotting the fraction of CBZ released in vitro and fraction absorbed showed a statistically significant relationship (R² = 0.935–0.975) for the three matrix tablets examined.

The purpose of this research was to mask the intensely bitter taste of primaquine phosphate (PRM) and to formulate suspension powder (cachets) of the taste masked drug. Taste masking was done using beta-cyclodextrin. To characterize and formulate taste masked cachets of PRM, the 1:25 M physical mixture was selected based on bitterness score. Phase solubility studies, fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Cachets were evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. Phase solubility studies showed weak interaction between PRM and CD. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, kneaded system and physical mixture exhibited better drug release at pH 1.2 and negligible effect at pH 6.8. Cachets prepared using physical mixture, (DS24), showed complete bitter taste masking and easy redispersibility. Taste evaluation of cachets in human volunteers rated tasteless with a score of 0 to DS24 and 3 to DS25. Thus, results conclusively demonstrated successful taste masking and formulation of cachets with taste masked drug.

The purpose of this research work was to formulate and characterize self-micro emulsifying drug delivery system containing exemestane. The solubility of exemestane was determined in various vehicles. Pseudo ternary phase diagram was used to evaluate the micro-emulsification existence area. SMEDDS formulations were tested for micro-emulsifying properties, and the resultant formulations loaded with exemestane (ME1, ME2, ME3, ME4 and ME5) were investigated for clarity, phase separation, globule size and shape, zeta potential, effect of various diluents and dilutions, thermodynamic and thermal stability. From the results it is concluded that increase in droplet size is proportional to the concentration of oil in SMEDDS formulation. Minor difference in the droplet size and zeta potential was observed by varying the diluents (deionized water and 0.1 N HCl) and dilutions (1:10, 1:50 and 1:100). Formulations, which were found to be thermodynamically stable (ME1, ME2, ME3 and ME4), were subjected to stability studies as per International Conference on Harmonization (ICH) guidelines. No significant variations were observed in the formulations over a period of 3 months at accelerated and long-term conditions. TEM photographs of microemulsions formulations further conformed the spherical shape of globules. Among the various SMEDDS formulations, ME4 offer the advantages of good clarity systems at high oil content and thus offer good solubilization of exemestane. Thus this study indicates that the SMEDDS can be used as a potential drug carrier for dissolution enhancement of exemestane and other lipophilic drug(s).

The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2–7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6–7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentration–time profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.

The stability of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and its potential incompatibility with active pharmaceutical ingredients (API) carrying hydroxyl group(s) were investigated in this research. HPMC-AS may undergo hydrolysis under harsh processing conditions with the generation of succinic acid and acetic acid, which can form ester bond(s) with the hydroxyl group(s) in API. In this case, the hot-melt extrusion (HME) product prepared from HPMC-AS and our model compound (compound A) was tested after heating at 140°C up to 5 h. The succinate esters of compound A and its epimer were found in the product, suggesting potential drug–excipient incompatibility during formulation development. In addition, dyphylline was also tested with HPMC-AS and the potential incompatibility was further confirmed.

The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 3² full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.

The purpose of this research was to investigate the physical characteristics and crystalline structure of bis(p-fluorobenzyl)trisulfide, a new anti-tumor agent. Methods used included X-ray single crystal diffraction, X-ray powder diffraction (XRPD), Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC) and thermogravimetric (TG) analyses. The findings obtained with X-ray single crystal diffraction showed that a monoclinic unit cell was a = 12.266(1) Å, b = 4.7757(4) Å, c = 25.510(1) Å, β = 104.25(1)°; cell volume = 1,448.4(2) Å³, Z = 4, and space group C2/c. The XRPD studies of the four crystalline samples, obtained by recrystallization from four different solvents, indicated that they had the same diffraction patterns. The diffraction pattern stimulated from the crystal structure data is in excellent agreement with the experimental results. In addition, the identical FT-IR spectra of the four crystalline samples revealed absorption bands corresponding to S–S and C–S stretching as well as the characteristic aromatic substitution. Five percent weight loss at 163.3 °C was observed when TG was used to study the decomposition process in the temperature range of 20–200 °C. DSC also allowed for the determination of onset temperatures at 60.4(1)–60.7(3) °C and peak temperatures at 62.1(3)–62.4(3) °C for the four crystalline samples studied. The results verified that the single crystal structure shared the same crystal form with the four crystalline samples investigated.

The purpose of this research was to develop an emulsion formulation of indomethacin (IND) suitable for nasal delivery. IND was incorporated into the oil phases of oil in water (O/W) and water in oil (W/O) emulsions. For this purpose, different emulsifying agents (Tween 80, Span 80 and Brij 58) were used in two emulsion formulations. When the effects of several synthetic membranes (nylon, cellulose, cellulose nitrate) were compared with the sheep nasal mucosa, the cellulose membrane and sheep nasal mucosa showed similar permeation properties for O/W emulsion (P > 0.05). To examine the absorption characteristics of IND, the anti-inflammatory properties of intravenous solution of IND, intranasal O/W emulsions of IND (with or without enhancers) and intranasal solution of IND (IND-Sol) were investigated in rats with carrageenan-induced paw edema. When citric acid was added to the nasal emulsion, the anti-inflammatory activity was similar to that of intravenous solution (P > 0.05). Finally, it was concluded that, intranasal administration of IND emulsion with citric acid may be considered as an alternative to intravenous and per oral administrations of IND to overcome their adverse effects.

The purpose of this study was to prepare wax-incorporated pectin-based emulsion gel beads using a modified emulsion-gelation method. The waxes in pectin–olive oil mixtures containing a model drug, metronidazole, were hot-melted, homogenized and then extruded into calcium chloride solution. The beads formed were separated, washed with distilled water and dried for 12 h. The influence of various types and amounts of wax on floating and drug release behavior of emulsion gel beads of calcium pectinate was investigated. The drug-loaded gel beads were found to float on simulated gastric fluid if the sufficient amount of oil was used. Incorporation of wax into the emulsion gel beads affected the drug release. Water-soluble wax (i.e. polyethylene glycol) increased the drug release while other water-insoluble waxes (i.e. glyceryl monostearate, stearyl alcohol, carnauba wax, spermaceti wax and white wax) significantly retarded the drug release. Different waxes had a slight effect on the drug release. However, the increased amount of incorporated wax in the formulations significantly sustained the drug release while the beads remained floating. The results suggest that wax-incorporated emulsion gel beads could be used as a carrier for intragastric floating drug delivery.

The purpose of this research was to develop and evaluate different preparations of sustained delivery systems, using Carbopols as carriers, in the form of matrices and three-layer tablets with isosorbite mononitrate. Matrix tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. The findings of the study indicated that all systems demonstrated sustained release. The properties of the polymer used and the structure of each formulation appear to considerably affect drug release and its release rate. The three-layer formulations exhibit lower drug release compared to the matrices. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug dissolution and release. The geometrical characteristics/structure of the tablets as well as the weight/thickness of the barriers-layers considerably influence the rate of drug release and the release mechanisms. Kinetic analysis of the data indicated that drug release from matrices was mainly attributed to Fickian diffusion while three-layer tablets exhibited either anomalous diffusion or erosion/relaxation mechanisms. The advantage of Carbopol formulations is that a range of release profiles can easily be obtained through variations in tablet structure and thus Carbopols are appropriate carriers of oral sustained drug delivery systems for soluble drugs such as the isosorbite mononitrate.

The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm². Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 μmol/cm²/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 μmol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.

The purpose of this research was to investigate the variability of the roller compaction process while monitoring in-line with near-infrared (NIR) spectroscopy. In this paper, a pragmatic method in determining this variability of in-line NIR monitoring roller compaction process was developed and the variability limits were established. Fast Fourier Transform (FFT) analysis was used to study the source of the systematic fluctuations of the NIR spectra. An off-line variability analysis method was developed as well to simulate the in-line monitoring process in order to determine the variability limits of the roller compaction process. For this study, a binary formulation was prepared composed of acetaminophen and microcrystalline cellulose. Different roller compaction parameters such as roll speed and feeding rates were investigated to understand the variability of the process. The best-fit line slope of NIR spectra exhibited frequency dependence only on the roll speed regardless of the feeding rates. The eccentricity of the rolling motion of rollers was identified as the major source of variability and correlated with the fluctuations of the slopes of NIR spectra. The off-line static and dynamic analyses of the compacts defined two different variability of the roller compaction; the variability limits were established. These findings were proved critical in the optimization of the experimental setup of the roller compaction process by minimizing the variability of NIR in-line monitoring.

Buccal bioadhesive films, releasing topical drugs in the oral cavity at a slow and predetermined rate, provide distinct advantages over traditional dosage forms. The aim of present study was to prepare and evaluate buccal bioadhesive films of clotrimazole for oral candidiasis. The film was designed to release the drug at a concentration above the minimum inhibitory concentration for a prolonged period of time so as to reduce the frequency of administration of the available conventional dosage forms. The different proportions of sodium carboxymethylcellulose and carbopol 974P (CP 974P) were used for the preparation of films. Carbopol was used to incorporate the desired bioadhesiveness in the films. The films were prepared by solvent casting method and evaluated for bioadhesion, in vitro drug release and effectiveness against Candida albicans. In vitro drug release from the film was determined using a modified Franz diffusion cell while bioadhesiveness was evaluated with a modified two-arm balance using rabbit intestinal mucosa as a model tissue. Films containing 5% CP 974P of the total polymer were found to be the best with moderate swelling along with favorable bioadhesion force, residence time and in vitro drug release. The microbiological studies revealed that drug released from the film could inhibit the growth of C. albicans for 6 h. The drug release mechanism was found to follow non-Fickian diffusion.

Photocrosslinked polyacrylic acid hydrogel, made from polyacrylic acid (PAA) modified with 2-hydroxyethyl methacrylate (HEMA), is a promising candidate adhesive for dermatological patches. In this study, we investigated the further availability of hydrogel as an adhesive for dermatological patches using a hydrogel containing indomethacin (IDM) as a model anti-inflammatory patch. From an orthogonal experimental study, we clarified the relationships between formulation factors and characteristics of model formulation. Formulations with a lower degree of swelling were prepared by increasing the degree of HEMA modification and the addition of Tween 80. Apparent permeation rate was increased by addition of l-menthol and Tween 80. A tendency for higher HEMA modification to be accompanied by the prolongation of the lag time of IDM was observed. To obtain an applicable anti-inflammatory patch, we conducted a formulation optimization study using a novel optimization method, a response-surface method incorporating multivariate spline interpolation (RSM-S). Consequently, a highly functional anti-inflammatory patch in terms of its adhesive properties and bioavailability was successfully obtained. Since a wide range of functions can be fully controlled by manipulating the formulation factors, photocrosslinked polyacrylic acid hydrogel is an attractive candidate adhesive for dermatological patches.

The aim of this study was to optimize and formulate fast disintegrating tablets (FDTs) for nausea and vomiting using aminoacetic acid, carmellose and sodium alginate with enough mechanical strength. Ondansetron HCl (water soluble) or domperidone (water insoluble) drug were added to FDTs and their disintegration behaviour was evaluated. Plackett Burman Screening Design was used to screen the independent active process variables [concentration of aminoacetic acid (X₁), concentration of carmellose (X₂) and tablet crushing strength (X₃)] which were found to actively influence the dependent variables [disintegration time in the mouth (DT), wetting time (WT), and water absorption ratio (WAR)] for both the drugs. Also, the coefficients of active variables (DT, WT and WAR) of FDTs containing domperidone was found to be significantly different (P < 0.05) from the coefficients of active factors (X₁, X₂ and X₃) containing ondansetron HCl FDTs. Further, FDTs containing domperidone was prepared according to central composite design for estimating the effect of active factors (X₁, X₂, X₃) in extended spherical domain. The regression analysis of quadratic fit revealed that DT, WT and WAR were 98% correlated with active factors (X₁, X₂ or X₃). The optimized domperidone FDTs were further compared with superdisintegrants (croscarmellose sodium or crospovidone). The data revealed that optimized domperidone FDTs were better than domperidone FDTs containing croscarmellose or crospovidone. Hence, this novel excipients combination can be used for delivery of water insoluble drugs in place of superdisintegrants.

The purpose of this research was to mask the bitter taste of Diphenhydramine Hydrochloride (DPH) using cation exchange resins. Indion 234 and Tulsion 343 that contained crosslinked polyacrylic backbone were used. The drug resin complexes (DRC) were prepared by batch process by taking drug: resin ratios 1:1, 1:2, and 1:3. The optimum drug: resin ratio and the time required for maximum complexation was determined. The drug resinates were evaluated for the drug content, taste, micromeritic properties drug release and X-ray diffraction (PXRD). Effervescent and dispersible tablets were developed from optimum drug: resin ratios of 1:2 and 1:1. The formulations were evaluated for uniformity of dispersion, disintegration time, and in vitro dissolution. The X-ray diffraction study confirmed the monomolecularity of entrapped drug in the resin beads. The taste evaluation depicted the successful taste masking of DPH with drug resin complexes. The drug release of 95% in 15 min was observed for effervescent and dispersible tablets.

The purpose of this study was to prepare and evaluate layered matrix tablets of propranolol HCl containing HPMC and phytowax as matrix component using direct compression technique. Layering with this polymeric matrix could prolong the release of drug and shift the release pattern approach to zero order as described from the least square curve fitting. Increasing the amount of coating layer could apparently prolong the drug release. The longer lag time of drug release from one planar apparently when the amount of coating layer was increased. HPMC concentration and compression force did not affect the drug release from this three-layer tablet. The drug release from this three-layer tablet was influenced by hydrodynamic force. An increase in stirring rate was a corresponding increasing in the release rate. From photoimage and SEM, gel mass of HPMC was increased with time during dissolution and covered the core surface, therefore dissolved drug molecules were allowed to diffuse out from the core through the polymer network of gel layer containing the porous structure. This suggested that HPMC and phytowax could be fabricated into the layered matrix tablet exhibiting sustained drug release.

The purpose of the present investigation is to formulate and evaluate proniosomal transdermal carrier systems for flurbiprofen. Proniosomes were prepared using various non-ionic surfactants, namely span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60) and span 80 (Sp 80) without and with cholesterol at percentages ranging from 0% to 50%. The effect of surfactant type and cholesterol content on drug release was investigated. Drug release was tested by diffusion through cellophane membrane and rabbit skin. Drug release from the prepared systems was compared to that from flurbiprofen suspensions in distilled water and HPMC (hydroxypropylmethylcellulose) gels. In case of Sp 20 and Sp 80, the added amount of cholesterol affected the preparation type to be either proniosomal alcoholic solutions or liquid crystalline gel systems. On the other hand, both Sp 40 and Sp 60 produced gel systems in presence or absence of cholesterol. Microscopic observations showed that either proniosomal solutions or gel formulations immediately converted to niosomal dispersions upon hydration. Due to the skin permeation barrier, rabbit skin showed lower drug diffusion rates compared to cellophane membrane. The proniosomal composition controlled drug diffusion rates to be either faster or slower than the prepared flurbiprofen suspensions in HPMC gels or distilled water, respectively. In conclusion, this study demonstrated the possibility of using proniosomal formulations for transdermal drug delivery.

The purpose of this research was to evaluate the variables that are suggested to influence the adsorption of the hydrophilic hyaluronic acid (HA) onto the surface of the hydrophobic betamethasone-17-valerate (BV) particles in order to formulate a nebulizable suspension. The adsorption of HA from aqueous solutions (0.04% to 0.16%, w/v) to a fixed BV concentration (0.04%, w/v) under different experimental conditions, was investigated. The method of preparation of HA-BV suspensions involved suspending BV particles either in the hydrated HA solution (method 1) or in water followed by addition of solid HA (method 2). Other variables like the time required for the adsorption to complete and temperature at which adsorption is carried out were studied. The nebulization of the suspensions was tested via an air jet nebulizer connected to a twin stage impinger. In order to improve the nebulization behavior of the optimized suspension, l-leucine or sodium taurocholate was incorporated in increasing concentrations (0.01–0.04%, w/v). The optimized suspension, having a nebulization efficiency of 33.75%, was achieved following the adsorption of HA (0.1%, w/v) onto BV particles adopting method 2 of preparation and extending for three days at 4 °C. Incorporation of either l-leucine or sodium taurocholate significantly decreased the aggregate size of the optimized suspension and consequently caused significant increases in the nebulization efficiency to reach 46.87% and 56.25%, respectively.

The purpose of the present investigation was to elucidate the influence of curing on different physical properties of Eudragit® NE and RS coating systems. Increased curing times resulted in decreased drug release rates from Eudragit® NE-coated beads. However, an increase in drug release rates was noticed at longer curing times and higher temperatures for the Eudragit® RS coating system. The surface morphological changes of the film-coated beads revealed that there were no visible macroscopic changes as a result of curing. The absence of any ibuprofen melting peak in the DSC thermograms of cured NE and RS coated beads confirmed that there was no surface crystallization of ibuprofen. These results indicated that the increase in drug release rates from RS coated pellets, when subjected to long curing times, resulted from loss of plasticizer. Free films of Eudragit® NE exhibited an increase in tensile strength with increased curing times, whereas Eudragit® RS free films showed a decrease in tensile strength beyond 4 h of curing at 70 and 90 °C. The film thicknesses and weights of free films of Eudragit® RS prepared with triethyl citrate plasticizer were found to change more dramatically with curing than did free films of Eudragit® RS prepared with ibuprofen as the plasticizer. An increase in pore volume was also observed with increased curing times for Eudragit® RS free films. Such changes with curing were shown to be due to the loss of plasticizer molecules, leading to the formation of molecular-scale voids and channels.

The aim of this research was to determine the reference ultrasonic velocity (v) and attenuation coefficient (α) for 2H, 3H-perfluoropentane (HPFP), 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-tetrafluoroethane (HFA-227) propellants, for the future purpose of characterising pressurised metered dose inhaler (pMDI) formulations using high-resolution ultrasonic spectroscopy (HRUS). Perfluoroheptane (PFH) was used as a reference material for HPFP. With its velocity and attenuation coefficient determined at 25 °C, HPFP was subsequently used as a reference for HFA-134a and HFA-227. It was found that there is a linear decline in ultrasonic velocity with an increase in temperature. As with HPFP, the ultrasonic velocity of HFA-134a and HFA-227 were successfully calculated at 25 °C. However, the difference in density and viscosity between reference and sample prevented accurate determination of reference attenuation coefficient for the hydrofluoroalkanes. With ultrasonic velocity alone, dispersion concentration and stability monitoring for experimental pMDI formulations is possible using HRUS. However, at this point in time measurement of particle size is not feasible.

The purpose of this research was to describe the application of lyophilization in the delivery of siRNA using cationic lipids by addressing the long-term formulation/stability issues associated with cationic lipids and to understand the mechanism of lyoprotection. siRNA liposomes complexes were formed in different potential cyro/lyoprotectants and subjected to either lyophilization or freeze thaw cycles. siRNA, liposomes and/or lipoplexes were tested for activity, SYBR Green I binding, cellular uptake and particle size. The lipoplexes when lyophilized in the presence of sugars as lyoprotectants could be lyophilized and reconstituted without loss of transfection efficacy but in ionic solutions they lost 65–75% of their functionality. The mechanism of this loss of activity was further investigated. The lyophilization process did not alter siRNA’s intrinsic biological activity as was evident by the ability of lyophilized siRNA to retain functionality and SYBR green I binding ability. While the lipoplex size dramatically increased (∼50–70 times) after lyophilization in the absence of non-ionic lyoprotectants. This increase in size correlated to the decrease in cellular accumulation of siRNA and a decrease in activity. In conclusion, siRNAs can be applied in cationic lipid lyophilized formulations and these complexes represent a potential method of increasing the stability of pre-formed complex.

The aim of this study was to prepare bi-layer tablet of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB) for the effective treatment of migraine. MTH and IB were formulated as immediate and sustained release layer respectively. MTH was formulated as immediate release layer by using various disintegrants like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum. Treated form of gellan gum and agar was prepared and compared for their disintegrant efficiency with other disintegrants. IB was formulated as sustained release layer using hydrophilic matrix (hydroxypropylmethylcellulose [HPMC K₄M]). The effect of concentration of hydrophilic matrix (HPMC K₄M), binder (polyvinylpyrollidone [PVP K₃₀]) and buffer (sodium bicarbonate) on IB release was studied. The dissolution study of sustained release layer showed that an increasing amount of HPMC or PVP K₃₀ results in reduced IB release. The inclusion of buffer (sodium bicarbonate) enhanced the release of IB from sustained release layer. The rational for formulation of bi-layer tablet of these two drugs in combination was (1) MTH increases the absorption of acidic non-steroidal anti-inflammatory drug (NSAID) by increasing gastric motility. So sequential release of MTH (as immediate release) and IB (as sustained release) was suitable for treatment of migraine. (2) MTH was degraded when prolonged contact with acidic NSAID. Bi-layer tablet was suitable for preventing direct contact of these two drugs and thus to maximize the efficacy of combination of two drugs for migraine.

This work investigates the effect of excipient particle size on compaction properties of brittle, plastic and viscoelastic materials with and without added lubricants. Sieve cuts of Microcrystalline cellulose (MCC), Starch and Dibasic calcium phosphate dihydrate were obtained by sieving, then samples were tested without lubrication or with added lubricant (0.5% Mg stearate mixed for either 5 or 30-min). Compacts were left overnight before testing. It was found that in the absence of lubricant, compact tensile strength (TS) was dependent on particle size only for starch. With Mg stearate, lubricant sensitivity shows a strong dependence on excipient particle size for both starch and MCC, where smaller particles are less affected by lubricant. Dibasic calcium phosphate dihydrate was not sensitive to lubricant even after 30 min mixing. This study highlights that in the absence of lubricant, initial particle size of excipients has no impact on compact strength not only for Dibasic calcium phosphate dihydrate (brittle), but also for MCC (plastic). On the other hand, TS is dependent on particle size both with or without added lubricant for starch (viscoelastic).

This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 °C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.

The purpose of the present study was to develop and characterize the chitosan sponges loading with doxycycline hyclate and their antibacterial activities. The pore density of chitosan sponge prepared with freeze drying technique was increased as the higher concentrated chitosan solution was used. The sponge prepared from 10% w/w of the chitosan solution and crosslinking with glutaraldehyde solution was utilized for loading with doxycycline hyclate. The drug release and sustainable antibacterial activity of fabricated sponge were assessed using dissolution test and agar diffusion test, respectively. Drug release from non-crosslinked sponge into phosphate buffer pH7.4 was slower than that from crosslinked sponge since the former could absorb the medium and form gel to retard the initial drug diffusion. Sustainable antibacterial activity of developed sponge was evident against S. aureus and E. coli. In conclusion, the in vitro release profile and antibacterial efficiency indicated that doxycycline hyclate could be sustained using chitosan sponge.

The purpose of this study was to investigate the effect of drug incorporation methods on the partitioning behavior of lipophilic drugs in parenteral lipid emulsions. Four lipophilic benzodiazepines, alprazolam, clonazepam, diazepam, and lorazepam, were used as model drugs. Two methods were used to incorporate drugs into an emulsion: dissolving the compound in the oil phase prior to emulsification (de novo emulsification), and directly adding a concentrated solution of drug in a solubilizer to the emulsion base (extemporaneous addition). Based on the molecular structures and determination of the oil and aqueous solubilities and the partition coefficients of the drugs, the lipophilicity was ranked as diazepam > clonazepam > lorazepam > alprazolam. Ultracentrifugation was used to separate the emulsion into four phases, the oil phase, the phospholipid-rich phase, the aqueous phase and the mesophase, and the drug content in each phase was determined. Partitioning of diazepam, which has the highest lipophilicity and oil solubility among the four drugs, was unaffected by the drug incorporation method, with both methods giving a high proportion of drug in the inner oil phase and the phospholipid-rich phase, compared to the aqueous phase and mesophase. Partitioning of the less lipophilic drugs (alprazolam, clonazepam, and lorazepam) in the phases of the emulsion system was dependent on the method of incorporation and the drug solubility properties. Emulsions of the three drugs prepared by de novo emulsification exhibited higher drug localization in the phospholipid-rich phase compared to those made by extemporaneous addition. With the latter method, the drugs tended to localize in the outer aqueous phase and mesophase, with less deposition in the phospholipid-rich phase and no partitioning into the inner oil phase.

The purpose of the study was to investigate the effect of drug solubility on polymer hydration and drug dissolution from modified release matrix tablets of polyethylene oxide (PEO). Different PEO matrix tablets were prepared using acetaminophen (ACE) and ibuprofen (IBU) as study compounds and Polyox® WSR301 (PEO) as primary hydrophilic matrix polymer. Tablet dissolution was tested using the USP Apparatus II, and the hydration of PEO polymer during dissolution was recorded using a texture analyzer. Drug dissolution from the preparations was dependent upon drug solubility, hydrogel formation and polymer proportion in the preparation. Delayed drug release was attributed to the formation of hydrogel layer on the surface of the tablet and the penetration of water into matrix core through drug dissolution and diffusion. A multiple linear regression model could be used to describe the relationship among drug dissolution, polymer ratio, hydrogel formation and drug solubility; the mathematical correlation was also proven to be valid and adaptable to a series of study compounds. The developed methodology would be beneficial to formulation scientists in dosage form design and optimization.

Physical properties (roughness, gloss, mechanical, surface topography and adhesive) of a bioadhesive film for the transdermal delivery of drugs and its interactions with a skin model surface were studied. Roughness is a measurement of the small-scale variations in the height of a physical surface. No significant differences in Ra between the “x” and “y” dimensions for both the skin model and patch were detected, due to uniformity in their production. Scanning electron microscope pictures showed small particles projected from the film. Those particles resulted in increasing roughness and surface area. For the patch, gloss values measured at 20° were 6.0 ± 0.9 and at 60°, 32.2 ± 2.2 gloss units, respectively, indicating a semi-gloss material. Concerning the mechanical properties, the tensile strength of the film resulted four- to sevenfold greater than the peel force from the model skin used, indicating the suitability of the film for skin application. The adhesion to skin model depended on the amount of water used for film application and on the elapsed time between film application and removal. Finally, the model skin that was invented by Charkoudian can be used as an alternative to costly and highly variable human skin substrates since it possesses human topography.

A gastro retentive floating drug delivery system with multiple-unit minitab’s based on gas formation technique was developed in order to prolong the gastric residence time and to increase the overall bioavailability of the drug. The system consists of the drug-containing core units prepared by direct compression process, which are coated with three successive layers of an inner seal coat, effervescent layer (sodium bicarbonate) and an outer gas-entrapped polymeric membrane of an polymethacrylates (Eudragit RL30D, RS30D, and combinations of them). Only the system using Eudragit RL30D and combination of them as a gas-entrapped polymeric membrane could float. The time to float decreased as amount of the effervescent agent increased and coating level of gas-entrapped polymeric membrane decreased. The optimum system floated completely within 3 min and maintained the buoyancy over a period of 12 h. The drug release was controlled and linear with the square root of time. Increasing coating level of gas-entrapped polymeric membrane decreased the drug release. Both the rapid floating and the controlled release properties were achieved in the multiple-unit floating drug delivery system developed in this present study. The analysis of the parameter dissolution data after storage at 40 °C and 75% RH for 3 months showed, no significant change indicating the two dissolution profiles were considered to be similar (f2 value is more than 50).

The purpose of this research was to prepare and evaluate sustained release mucoadhesive tablets of Itraconazole. It is practically insoluble in aqueous fluids hence its solid dispersion with Eudragit E100 was prepared by spray drying. This was formulated in matrix of hydrophilic mucoadhesive polymers Carbopol 934P (CP) and Methocel K4M (HPMC). The formulation was optimized using a 3² factorial design. Amounts of CP and HPMC were taken as formulation variables for optimizing response variables i.e. mucoadhesion and dissolution parameters. The optimized mucoadhesive formulation was orally administered to albino rabbits, and blood samples collected were used to determine pharmacokinetic parameters. The solid dispersion markedly enhanced the dissolution rate of itraconazole. The bioadhesive strength of formulation was found to vary linearly with increasing amount of both polymers. Formulations exhibited drug release fitting Peppas model with value of n ranging from 0.61 to 1.18. Optimum combination of polymers was arrived at which provided adequate bioadhesive strength and fairly regulated release profile. The experimental and predicted results for optimum formulations were found to be in close agreement. The formulation showed C_max 1898 ± 75.23 ng/ml, t_max of the formulation was 2 h and AUC was observed to be 28604.9 ng h/ml

The objective was to investigate the suitable polymeric films for the development of diltiazem hydrochloride (diltiazem HCl) transdermal drug delivery systems. Hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) were used as hydrophilic and hydrophobic film formers, respectively. Effects of HPMC/EC ratios and plasticizers on mechanical properties of free films were studied. Effects of HPMC/EC ratios on moisture uptake, in vitro release and permeation through pig ear skin of diltiazem HCl films were evaluated. Influence of enhancers including isopropyl myristate (IPM), isopropyl palmitate (IPP), N-methyl-2-pyrrolidone, oleic acid, polyethylene glycol 400, propylene glycol, and Tween80 on permeation was evaluated. It was found that addition of EC into HPMC film produced lower ultimate tensile strength, percent elongation at break and Young’s modulus, however, addition of EC up to 60% resulted in too hard film. Plasticization with dibutyl phthalate (DBP) produced higher strength but lower elongation as compared to triethyl citrate. The moisture uptake and initial release rates (0–1 h) of diltiazem HCl films decreased with increasing the EC ratio. Diltiazem HCl films (10:0, 8:2 and 6:4 HPMC/EC) were studied for permeation because of the higher release rate. The 10:0 and 8:2 HPMC/EC films showed the comparable permeation-time profiles, and had higher flux values and shorter lag time as compared to 6:4 HPMC/EC film. Addition of IPM, IPP or Tween80 could enhance the fluxes for approx. three times while Tween80 also shorten the lag time. In conclusion, the film composed of 8:2 HPMC/EC, 30% DBP and 10% IPM, IPP or Tween80 loaded with 25% diltiazem HCl should be selected for manufacturing transdermal patch by using a suitable adhesive layer and backing membrane. Further in vitro permeation and in vivo performance studies are required.

The purpose of this study was to develop a lyotropic liquid crystalline formulation using the emulsifier vitamin E TPGS and evaluate its behavior after incorporation of a flavonoid, quercetin. The physical (macro and microscopic), chemical (determination of quercetin content by the HPLC method) and functional (determination of quercetin antioxidant activity by DPPH^• assay) stability of the lamellar liquid crystalline formulation containing flavonoid was evaluated when stored at 4 ± 2 °C; 30 ± 2 °C/70 ± 5% RH (relative humidity) and 40 ± 2 °C/70 ± 5% RH during 12 months. The lamellar liquid crystalline structure of the formulation was maintained during the experiment, however chemical and functional stability results showed a great influence of the storage period in all conditions tested. A significant decrease in quercetin content (approximately 40%) was detected during the first month of storage and a similar significant loss in antioxidant activity was detected after 6 months. The remaining flavonoid content was unchanged during the final 6 months of the experimental period. The results suggest possible interactions between quercetin and the liquid crystalline formulation, which could inhibit or reduce the quercetin activity incorporated in the system. In conclusion, the present study demonstrated that incorporation of quercetin (1%) did not affect the liquid crystalline structure composed of vitamin E TPGS/IPM/PG–H₂O (1:1) at 63.75/21.25/15 (w/w/w). Nevertheless, of the total quercetin incorporated in the system only 60% was free to act as an antioxidant.

Purpose

To develop a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of a wide variety of therapeutics including paclitaxel.

Methods

Chitosan/GMO nanoparticles were prepared by multiple emulsion (o/w/o) solvent evaporation methods. Particle size and surface charge were determined. The morphological characteristics and cellular adhesion were evaluated with surface or transmission electron microscopy methods. The drug loading, encapsulation efficiency, in vitro release and cellular uptake were determined using HPLC methods. The safety and efficacy were evaluated by MTT cytotoxicity assay in human breast cancer cells (MDA-MB-231).

Results

These studies provide conceptual proof that chitosan/GMO can form polycationic nano-sized particles (400 to 700 nm). The formulation demonstrates high yields (98 to 100%) and similar entrapment efficiencies. The lyophilized powder can be stored and easily be resuspended in an aqueous matrix. The nanoparticles have a hydrophobic inner-core with a hydrophilic coating that exhibits a significant positive charge and sustained release characteristics. This novel nanoparticle formulation shows evidence of mucoadhesive properties; a fourfold increased cellular uptake and a 1000-fold reduction in the IC₅₀ of PTX.

Conclusion

These advantages allow lower doses of PTX to achieve a therapeutic effect, thus presumably minimizing the adverse side effects.

The release of propranolol hydrochloride from matrix tablets with hydroxy propyl methyl cellulose (HPMC K15M) or Kollidon®SR at different concentrations was investigated with a view to developing twice daily sustained release dosage form. A hydrophilic matrix-based tablet using different concentrations of HPMC K15M or Kollidon®SR was developed using direct compression technique to contain 80 mg of propranolol hydrochloride. The resulting matrix tablets prepared with HPMC K15M or Kollidon®SR fulfilled all the official requirements of tablet dosage forms. Formulations were evaluated for the release of propranolol hydrochloride over a period of 12 h in pH 6.8 phosphate buffer using USP type II dissolution apparatus. Propranolol hydrochloride and pure Kollidon®SR or HPMC K15M compatibility interactions was investigated by using Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopic and DSC studies revealed that there was no well defined chemical interaction between propranolol hydrochloride with Kollidon®SR or HPMC K15M. Tablets were exposed to 40 °C/75% of RH in open disc for stability. The in vitro drug release study revealed that HPMC K15 at a concentration of 40% of the dosage form weight was able to control the release of propranolol hydrochloride for 12 h, exhibit non-Fickian diffusion with first-order release kinetics where as at 40% Kollidon®SR same dosage forms show zero-order release kinetics. In conclusion, the in vitro release profile and the mathematical models indicate that release of propranolol hydrochloride can be effectively controlled from a single tablet using HPMC K15M or Kollidon®SR matrix system.

The aim of this study was to investigate an influence of different types of membrane additives including negative charge (dicetylphosphate, DCP), positive charge (stearylamine, STR) and non-ionic molecule (cholesteryl poly-24-oxyethylene ether, SC24) on the physicochemical properties of drug-free and drug-loaded niosomes. Salicylic acid having different proportions of ionized and unionized species at different pH was selected as a model drug. The niosomes were composed of 1:1 mole ratio of Span 60: cholesterol as vesicle forming agents. The results show that incorporation of salicylic acid to the niosomes did not affect zeta potential values; however, addition of the membrane additives changed the zeta potential depending on the type of the additives. Transmission electron microscopy revealed that niosomes had unilamellar structure. The particle sizes of all developed niosomes were between 217 to 360 nm. The entrapment efficiency (%E.E.) of all salicylic acid niosomes at pH 3 was higher than that of niosomes at pH 5, indicating that salicylic acid in unionized form was preferably incorporated in niosomes. Furthermore, the positively charged niosomes showed the highest %E.E. of salicylic acid owing to electrostatic attraction between STR and salicylic acid. After 3 months of storage at 4°C, the particle size of the niosomes remained in the nanosize range except for DCP salicylic acid niosomes at pH 3 whose size increased due to an instability of DCP at low pH. In addition, all niosomes showed no leakage of the salicylic acid after 3 months of storage indicating the good stability.

The purpose of present study was to evaluate commercial preparations of carbamazepine tablets with respect to drug release through a defined sequence of experiments using Minitab software. The compliance of products with respect to United States Pharmacopeia (USP) dissolution test and comparison of the products with respect to drug release in different dissolution conditions is reported in the present paper. The different dissolution conditions studied include dissolution medium (1% SLS in purified water, 0.1 N HCl), volume (900 and 1,000 ml), rpm (50 rpm, 75 rpm). Studies indicated that all six products complied with USP dissolution criteria. However, the extent of influence of dissolution conditions on drug release was varied among the products. Distinct dissolution profiles were observed and there was no correlation with disintegration time in certain products. The in vitro dissolution experimentation helped in identifying the discriminatory dissolution conditions and also the formulations that were unaffected with change of dissolution variables. In summary, commercial preparations of carbamazepine vary widely in their dissolution behavior in multi dissolution run experimentation. Identifying this behavior of the products was essential as an in vitro tool for screening a good and a bad formulation.

The present investigation aims at studying the effect of mixed surfactant system of sodium lauryl sulphate (SLS) and alkyl polyglucosides (C₁₀APG, C₁₂APG and C_12/14APG) on dissolution rate enhancement of poorly water soluble drug. Aceclofenac—a non-steroidal anti-inflammatory agent was used as a model drug as it has limited water solubility. The influence of the surfactant concentration in various blends on dissolution rate of Solid Dispersion (SD), prepared using solution method with ethanol as the solvent was studied and the advantage of mixed surfactant systems over the individual surfactants was illustrated by differences in the in-vitro dissolution profiles of SD. Physico chemical evaluation (critical micellar concentration, zeta potential and β-parameter calculations) was carried out to study the mixed surfactant systems. Solid mixtures were characterized by Infrared spectroscopy (FT-IR); X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). It was seen that the dissolution rate of aceclofenac from SD increased with the increase in the APG proportion relative to SLS with the optimum ratio of 0.2 SLS:0.8 APG showing the best effect in all cases. Results obtained from physico-chemical evaluation (the decrease in the value of critical micelle concentration and higher negative value of β-parameters) suggested the existence of synergism between surfactants blends. The observed results in the dissolution rate enhancement could be attributed to the drug—surfactant interactions as evident from FT-IR, SEM and XRD results.

The aim of this study was to investigate a newly synthesized dextrin–zidovudine (AZT) conjugate designed as a sustained release prodrug of AZT for parenteral administration. AZT was first reacted with succinic anhydride to form a succinoylated AZT which was subsequently coupled with dextrin to yield the dextrin–AZT conjugate. The structure of the conjugate was characterized by FT-IR and ¹H-NMR spectroscopy. The drug content of the conjugate was 18.9 wt.%. The release in vitro of free AZT and succinoylated AZT was investigated in buffer solutions at pH 5.5 and 7.4 and in human plasma. AZT and succinoylated AZT release from the conjugate was 1.4% (pH 5.5), 41.7% (pH 7.4) and 78.4% in human plasma after 24 h. Release was complete in human plasma after 48 h. A pharmacokinetic study in rats following intravenous administration of the conjugate showed prolonged plasma levels of AZT compared to free AZT. The use of the conjugate extended the plasma half-life of AZT from 1.3 to 19.3 h and the mean residence time from 0.4 to 23.6 h. Furthermore, the conjugate provided a significant greater area under the plasma concentration-time curve and reduced the systemic clearance of AZT. This study suggested the potential of this novel dextrin–AZT conjugate as a new intravenous preparation of AZT.

The aim of this study was to investigate the influence of polymer level and type of some hydrophobic polymers, including hydrogenated castor oil (HCO); Eudragit RS100 (E-RS100); Eudragit L100 (E-L100), and some fillers namely mannitol [soluble filler], Dibasic calcium phosphate dihydrate (Emcompress) and anhydrous dibasic calcium phosphate [insoluble fillers] on the release rate and mechanism of baclofen from matrix tablets prepared by a hot-melt granulation process (wax tablets) and wet granulation process (E-RS100 and E-L100 tablets). Statistically significant differences were found among the drug release profile from different classes of polymeric matrices. Higher polymeric content (40%) in the matrix decreased the release rate of drug because of increased tortuosity and decreased porosity. At lower polymeric level (20%), the rate and extent of drug release was elevated. HCO was found to cause the strongest retardation of drug. On the other hand, replacement of Emcompress or anhydrous dibasic calcium phosphate for mannitol significantly retarded the release rate of baclofen, except for E-L100 (pH-dependent polymer). Emcompress surface alkalinity and in-situ increase in pH of the matrix microenvironment enhanced the dissolution and erosion of these matrix tablets. The release kinetics was found to be governed by the type and content of the excipients (polymer or filler). The prepared tablets showed no significant change in drug release rate when stored at ambient room conditions for 6 months.

The purpose of this investigation was to determine the mechanism of interaction between ketotifen fumarate and chitosan at different pH values. The specific surface area of chitosan was determined using gas sorption analyzer. The sorption experiments were conducted at pH 7 and 10 using two different particle size ranges of chitosan. The solutions were prepared at constant ionic strength and buffer concentration, with only varying the pH. The rotating bottle method was used for measuring the sorption. The average specific surface areas for the two different particle size ranges of chitosan were found to be 4.56 and 0.74 m²/g. The Langmuir-like equation and a model independent equation were both applied to the sorption experimental data. The extent of ketotifen uptake at pH 7 for small and large particles of chitosan was found to be 1,073 and 2,204 mg/g respectively. While the extent of ketotifen uptake at pH 10 for small and large particles of chitosan was found to be 4 and 11 mg/g respectively. The aforementioned results indicated that sorption of ketotifen fumarate at pH 7 is extremely high compared to pH 10 and that the sorption increases by decreasing the specific surface area of chitosan. Based on the results obtained, the following conclusions were reached. Ketotifen might be absorbed into the bulk structure of chitosan in addition to being adsorbed on the surface and the ability of chitosan to swell at pH 7 has a significant role in increasing its uptake.

The purpose of this research was to mask the intensely bitter taste of artemether (ARM) and to formulate a rapid-disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by solid dispersion with mono amino glycyrrhyzinate pentahydrate (GLY) by solvent evaporation method. To characterize and formulate taste masked rapid disintegrating tablets (RDTs) of ARM, the 1:1M solid dispersion was selected based on bitterness score. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. RDTs were evaluated for weight variation, disintegration time, hardness and friability. In vitro drug release studies were performed for RDTs at pH 1.2 and 6.8. Bitterness score was evaluated using mini-column method and compared with gustatory sensation test. FTIR spectroscopy and DSC showed no interaction while XRPD showed amorphization of ARM in GLY solid dispersion. RDTs prepared using solid dispersion, (RDT3), showed faster disintegration (within 28 s) and complete bitter taste masking of ARM. In addition, RDT3 exhibited better dissolution profile at both pH 1.2 and 6.8, than RDTs prepared from pure ARM (RDT5). Taste evaluation of RDTs in human volunteers rated tasteless with a score of 0 to RDT3 and 3 to RDT5. Mini-column revealed that RDT5 showed increase in number of persons who sensed bitterness with increased amount of ARM release while RDT3 sensed no bitterness. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity with improved dissolution.

The purpose of this paper was to develop a statistical methodology to optimize tablet manufacturing considering drug chemical and physical properties applying a crossed experimental design. The assessed model drug was dried ferrous sulphate and the variables were the hardness and the relative proportions of three excipients, binder, filler and disintegrant. Granule properties were modeled as a function of excipient proportions and tablet parameters were defined by the excipient proportion and hardness. The desirability function was applied to achieve optimal values for excipient proportions and hardness. In conclusion, crossed experimental design using hardness as the only process variable is an efficient strategy to quickly determine the optimal design process for tablet manufacturing. This method can be applied for any tablet manufacturing method.

The aim of this review paper is to compare the potential of various techniques developed for production of homogenous, stable liposomes. Traditional techniques, such as Bangham, detergent depletion, ether/ethanol injection, reverse-phase evaporation and emulsion methods, were compared with the recent advanced techniques developed for liposome formation. The major hurdles for scaling up the traditional methods are the consumption of large quantities of volatile organic solvent, the stability and homogeneity of the liposomal product, as well as the lengthy multiple steps involved. The new methods have been designed to alleviate the current issues for liposome formulation. Dense gas liposome techniques are still in their infancy, however they have remarkable advantages in reducing the use of organic solvents, providing fast, single-stage production and producing stable, uniform liposomes. Techniques such as the membrane contactor and heating methods are also promising as they eliminate the use of organic solvent, however high temperature is still required for processing.

In order to develop a novel transdermal drug delivery system that facilitates the skin permeation of finasteride encapsulated in novel lipid-based vesicular carriers (ethosomes)finasteride ethosomes were constructed and the morphological characteristics were studied by transmission electron microscopy. The particle size, zeta potential and the entrapment capacity of ethosome were also determined. In contrast to liposomes ethosomes were of more condensed vesicular structure and they were found to be oppositely charged. Ethosomes were found to be more efficient delivery carriers with high encapsulation capacities. In vitro percutaneous permeation experiments demonstrated that the permeation of finasteride through human cadaver skin was significantly increased when ethosomes were used. The finasteride transdermal fluxes from ethosomes containing formulation (1.34 ± 0.11 μg/cm²/h) were 7.4, 3.2 and 2.6 times higher than that of finasteride from aqueous solution, conventional liposomes and hydroethanolic solution respectively (P < 0.01).Furthermore, ethosomes produced a significant (P < 0.01) finasteride accumulation in the skin, especially in deeper layers, for instance in dermis it reached to 18.2 ± 1.8 μg/cm². In contrast, the accumulation of finasteride in the dermis was only 2.8 ± 1.3 μg/cm² with liposome formulation. The study demonstrated that ethosomes are promising vesicular carriers for enhancing percutaneous absorption of finasteride.

Practical examples of preformulation support of the form selected for formulation development are provided using several drug substances (DSs). The examples include determination of the solubilities vs. pH particularly for the range pH 1 to 8 because of its relationship to gastrointestinal (GI) conditions and dissolution method development. The advantages of equilibrium solubility and trial solubility methods are described. The equilibrium method is related to detecting polymorphism and the trial solubility method, to simplifying difficult solubility problems. An example of two polymorphs existing in mixtures of DS is presented in which one of the forms is very unstable. Accelerating stability studies are used in conjunction with HPLC and quantitative X-ray powder diffraction (QXRD) to demonstrate the differences in chemical and polymorphic stabilities. The results from two model excipient compatibility methods are compared to determine which has better predictive accuracy for room temperature stability. A DSC (calorimetric) method and an isothermal stress with quantitative analysis (ISQA) method that simulates wet granulation conditions were compared using a 2 year room temperature sample set as reference. An example of a pH stability profile for understanding stability and extrapolating stability to other environments is provided. The pH-stability of omeprazole and lansoprazole, which are extremely unstable in acidic and even mildly acidic conditions, are related to the formulation of delayed release dosage forms and the resolution of the problem associated with free carboxyl groups from the enteric coating polymers reacting with the DSs. Dissolution method requirements for CR dosage forms are discussed. The applicability of a modified disintegration time (DT) apparatus for supporting CR dosage form development of a pH sensitive DS at a specific pH such as duodenal pH 5.6 is related. This method is applicable for DSs such as peptides, proteins, enzymes and natural products where physical observation can be used in place of a difficult to perform analytical method, saving resources and providing rapid preformulation support.

The aim of this work was the development of extended release tablets of 500 mg of ciprofloxacin based on swellable drug polyelectrolyte matrices (SDPM). A set of complexes of carbomer, ciprofloxacin and sodium, (CB–Cip)₅₀Na_x, having a molar ratio Cip/CB acid groups of 0.5 and variable proportions of Na⁺ was used to prepare SDPM. Characterization of complexes by FT-IR, powder X-ray diffraction and thermal analysis revealed that Cip, in its protonated form, is ionically bonded to the functional groups of CB. Rates of fluid uptake of (CB–Cip)₅₀Na_x matrices as well as Cip release in simulated gastric fluid were modulated by changes in the proportion of Na⁺ incorporated in the complexes. A direct correlation between fluid uptake and delivery rate was observed along the series of matrices. Release rates were modulated from 1.4 mg/min to 25 mg/min in going from (CB–Cip)₅₀Na₁₀ to (CB–Cip)₅₀Na₁₄. The analysis of kinetic data suggest that rates of swelling, ionic pair dissociation and drug diffusion play a role in the kinetic control of delivery. Complexes were satisfactorily prepared and processed together with small amounts of antiadherent and lubricant excipients to obtain a series of extended release SDPM tablets through the current tableting technology processes. Cip release from matrices was widely modulated by the composition of the complexes yielding a flexible system that allows selecting a composition that releases in 120 min 90% of the dose in simulated gastric fluid.

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal patches of sumatriptan succinate using chitosan as the base matrix. The patches were prepared by the solvent casting method. Gelatin and polyvinyl pyrrolidone (PVP) K30 were incorporated into the patches, to improve the film properties of the patches. The patches were found to be smooth in appearance, uniform in thickness, weight, and drug content; showed good mucoadhesive strength; and good folding endurance. A 3² full factorial design was employed to study the effect of independent variables viz. levels of chitosan and PVP K30, which significantly influenced characteristics like swelling index, in-vitro mucoadhesive strength, in vitro drug release, and in-vitro residence time. Different penetration enhancers were tried to improve the permeation of sumatriptan succinate through buccal mucosa. Formulation containing 3% dimethyl sulfoxide showed good permeation of sumatriptan succinate through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for administration of sumatriptan succinate.

The physical–chemical properties of interest for Controlled Release (CR) dosage form development presented are based on the author’s experience. Part I addresses selection of the final form based on a logical progression of physical–chemical properties evaluation of candidate forms and elimination of forms with undesirable properties from further evaluation in order to simplify final form selection. Several candidate forms which could include salt, free base or acid, polymorphic and amorphic forms of a new chemical entity (NCE) or existing drug substance (DS) are prepared and evaluated for critical properties in a scheme relevant to manufacturing processes, predictive of problems, requiring small amounts of test materials and simple analytical tools. A stability indicating assay is not needed to initiate the evaluation. This process is applicable to CR and immediate release (IR) dosage form development. The critical properties evaluated are melting, crystallinity, solubilities in water, 0.1 N HCl, and SIF, hygrodymamics, i.e., moisture sorption and loss at extremes of RH, and LOD at typical wet granulation drying conditions, and processability, i.e., corrosivity, and filming and/or sticking upon compression.

The purpose of this research was to evaluate a new wireless and battery-free sensor technology for invasive product temperature measurement during freeze-drying. Product temperature is the most critical process parameter in a freeze-drying process, in particular during primary drying. The product temperature over time profile and a precise detection of the endpoint of ice sublimation is crucial for comparison of freeze-drying cycles. Traditionally, thermocouples are used in laboratory scale units whereas resistance thermal detectors are applied in production scale freeze-dryers to evaluate temperature profiles. However, both techniques show demerits with regard to temperature comparability and biased measurements relative to vials without sensors. A new generation of wireless temperature sensors (Temperature Remote Interrogation System, TEMPRIS) were used in this study to investigate for the first time their value when applied to freeze-drying processes. Measurement accuracy, capability of accurate endpoint detection and effect of positioning were delineated by using product runs with sucrose, mannitol and trehalose. Data were compared to measurements with 36-gauge thermocouples as well as to non-invasive temperature measurement from Manometric Temperature Measurements. The results show that the TEMPRIS temperature profiles were in excellent agreement to thermocouple data when sensors were placed center bottom in a vial. In addition, TEMPRIS sensors revealed more reliable temperature profiles and endpoint indications relative to thermocouple data when vials in edge position were monitored. The results of this study suggest that TEMPRIS may become a valuable tool for cycle development, scale-up and routine manufacturing in the future.

The purpose of this study is to formulate in situ implants containing doxycycline hydrochloride and/or secnidazole that could be used in the treatment of periodontitis by direct periodontal intrapocket administration. Biodegradable polymers [poly (lactide) (PLA) and poly (lactide-co-glycolide) (PLGA)], each polymer in two concentrations 25%w/w, 35%w/w were used to formulate the in situ implants. The rheological behavior, in vitro drug release and the antimicrobial activity of the prepared implants were evaluated. Increasing the concentration of each polymer increases the viscosity and decreases the percent of the drugs released after 24 h. PLA implants showed a slower drugs release rate than PLGA implants in which the implants composed of 25% PLGA showed the fastest drugs release. The in vitro drug release and antimicrobial activity results were compared with results of Atridox®. Results revealed that the pharmaceutical formulation based on 25% PLGA containing secnidazole and doxycycline hydrochloride has promising activity in treating periodontitis in comparison with Atridox®.

Two numerical methods, Decision Analysis (DA) and Potential Problem Analysis (PPA) are presented as alternative selection methods to the logical method presented in Part I. In DA properties are weighted and outcomes are scored. The weighted scores for each candidate are totaled and final selection is based on the totals. Higher scores indicate better candidates. In PPA potential problems are assigned a seriousness factor and test outcomes are used to define the probability of occurrence. The seriousness-probability products are totaled and forms with minimal scores are preferred. DA and PPA have never been compared to the logical-elimination method. Additional data were available for two forms of McN-5707 to provide complete preformulation data for five candidate forms. Weight and seriousness factors (independent variables) were obtained from a survey of experienced formulators. Scores and probabilities (dependent variables) were provided independently by Preformulation. The rankings of the five candidate forms, best to worst, were similar for all three methods. These results validate the applicability of DA and PPA for candidate form selection. DA and PPA are particularly applicable in cases where there are many candidate forms and where each form has some degree of unfavorable properties.

The purpose of this study was to investigate the formulation variables influencing the drug release from the layered tablets containing chitosan and xanthan gum as matrix component. Increasing the amount of lactose could diminish pH sensitive release behavior of these matrix tablets. Effect of formulation variables on drug release from the prepared three-layered matrix tablets was investigated. The amount of drug loading did not affect the drug release which was influenced by the hydrodynamic force and the matrix composition. An increase in stirring rate correspondingly increased the release rate. Moreover, incorporation of soluble diluents in core or barrier could enhance the drug release. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi’s and zero order) was carried out to study the drug release mechanism. Most dissolution profiles of the prepared three-layered tablets provided a better fit to zero order kinetic than to first order kinetic and Higuchi’s equation.

The potential of poly(ethylene oxide)-poly(propylene oxide) block copolymers Pluronic® F127 (PF127) and Tetronic® 304 (T304), 904 (T904) and 1307 (T1307) as components of solid self-(micro)emulsifying dosage forms, S(M)EDDS, was evaluated. The dependence of the self-associative properties of Tetronics on pH explained the low ability of the micelles to solubilize griseofulvin at acid pH (sevenfold increase) compared to at alkaline pH (12-fold). Blends of polyglycolyzed glycerides (Labrasol, Labrafac CC, and Labrafil M 1944CS) with each copolymer at two different weight ratios (80:20 and 60:40) were prepared, diluted in water, and characterized in terms of globule size, appearance and griseofulvin solubility. The blends with Labrasol led to microemulsions that are able to increase drug solubility up to 30-fold. SMEDD hard gelatine capsules filled with griseofulvin and Labrasol or Labrasol/copolymer 80:20 showed a remarkable increase in drug solubility and dissolution rate, particularly when T904, T1307 or PF127 was present in the blend. This effect was more remarkable when the volume of the dissolution medium was 200 ml (compared to 900 ml), which can be related to a higher stability of the microemulsion when there is a greater concentration of the copolymer and glyceride in the medium.

The purpose of this research was to elucidate the significance of the changes in the mechanical and the volumetric properties on the moisture diffusivity through the polymer films. The internal stress concept was adapted and applied to estimate the relative impact of these property changes on the total stress experienced by a polymer film during storage. Hydroxypropyl Methylcellulose free films were used as a model material prepared at various conditions and stored at different relative humidities. The changes in the internal stress of these films due to the moisture sorption were studied. It was demonstrated that the stress-relaxation of the films increases at increasing moisture content. At the point when there is a definite loss of stress in the film, which is at moisture content higher than 6%, was shown to correlate with the significant increase of the moisture diffusivity. Further investigations revealed that the loss of stress is especially due to the swelling of the polymer rather than the changes in the inherent strain (the quotient between the tensile strength and the modulus of elasticity) of the HPMC films. This implies that the impact of the moisture sorption on the diffusivity is predominantly via volume addition rather than via altering the mechanical properties. Additionally, the approach presented here also brings up a new application of the internal stress concept, which in essence suggests the possibility to estimate the diffusion coefficient from the sorption isotherm and the mechanical analysis data.

This work was aimed at evaluating the effect of a pharmaceutical cationic exchange resin (Amberlite IRP-69) on the properties of controlled release matrices using Methocel K4M (HPMC) or Ethocel 7cP (EC) as matrix formers. Diphenhydramine hydrochloride (DPH), which was cationic and water soluble, was chosen as a model drug. HPMC- and EC-based matrices with varying amounts (0–40%w/w) of resin incorporation were prepared by a direct compression. Matrix properties including diameter, thickness, hardness, friability, surface morphology and drug release were evaluated. The obtained matrices were comparable in diameter and thickness regardless of the amount of resin incorporation. Increasing the incorporated resin decreased the hardness of HPMC- and EC-based matrices, correlating with the degree of rupturing on the matrix surfaces. The friability of HPMC-based matrices increased with increasing the incorporated resin, corresponding to their decreased hardness. In contrast, the EC-based matrices showed no significant change in friability in spite of decreasing hardness. The incorporated resin differently influenced DPH release from HPMC- and EC-based matrices in deionized water. The resin further retarded DPH release from HPMC-based matrices due to the gelling property of HPMC and the ion exchange property of the resin. In contrast, the release from EC-based matrices initially increased because of the disintegrating property of the resin, but thereafter declined due to the complex formation between released drug and dispersed resin via the ion exchange process. The release in ionic solutions was also described. In conclusion, the incorporated resin could alter the release and physical properties of matrices.

Mucociliary clearance (MC) is an important defense mechanism of the respiratory system to eliminate inhaled and possibly noxious particles from the lung. Although the principal mechanics of MC seem to be relatively clear there are still open questions regarding the long-term clearance of particles. Therefore, we have developed a new set-up based on embryonic chicken trachea (ECT) to investigate mucociliary particle clearance in more detail. ECT was placed in an incubation chamber after carbon particles were applied and tracked using optical microscopy. The aim of the study was to validate this model by investigating the impact of temperature, humidity and drugs on particle transport rates. Particles were transported reproducibly along the trachea and clearance velocity (2.39 ± 0.25) mm/min was found to be in accordance to data reported in literature. Variation in temperature resulted in significantly reduced MC: (0.40 ± 0.12) mm/min (20 °C); (0.42 ± 0.10) mm/min (45 °C). Decreasing humidity (99–60%) had no significant effect on MC, whereas reduction to 20% humidity showed a significant influence on particle clearance. The use of different cilio- and muco-active drugs (Propranolol, Terbutalin, N-acetylcysteine) resulted in altered MC according to the pharmacological effect of the substances: a concentration dependent decrease of MC was found for Propranolol. From our results we conclude that this model can be employed to investigate MC of particles in more detail. Hence, the model may help to understand and identify decisive physico-chemical parameters for MC and to answer open questions regarding the long-term clearance phenomenon.

The present study was undertaken to evaluate the gum exudates of Terminalia catappa Linn. (TC gum) as a release retarding excipient in oral controlled drug delivery system. The rheological properties of TC gum were studied and different formulation techniques were used to evaluate the comparative drug release characteristics. The viscosity was found to be dependent on concentration and pH. Temperature up to 60°C did not show significant effect on viscosity. The rheological kinetics evaluated by power law, revealed the shear thinning behavior of the TC gum dispersion in water. Matrix tablets of TC gum were prepared with the model drug dextromethorphan hydrobromide (DH) by direct compression, wet granulation and solid dispersion techniques. The dissolution profiles of the matrix tablets were compared with the pure drug containing capsules using the USP Basket apparatus with 500 ml phosphate buffer of pH 6.8 as a dissolution medium. The drug release from the compressed tablets containing TC gum was comparatively sustained than pure drug containing capsules. Even though all the formulation techniques showed reduction of dissolution rate, aqueous wet granulation showed the maximum sustained release of more than 8 h. The release kinetics estimated by the power law revealed that the drug release mechanism involved in the dextromethorphan matrix is anomalous transport as indicated by the release exponent n values. Thus the study confirmed that the TC gum might be used in the controlled drug delivery system as a release-retarding polymer.

The purpose of this study was to design and build a supercritical CO₂ anti-solvent (SAS) unit and use it to produce microparticles of the class II drug carbamazepine. The operation conditions of the constructed unit affected the carbamazepine yield. Optimal conditions were: organic solution flow rate of 0.15 mL/min, CO₂ flow rate of 7.5 mL/min, pressure of 4,200 psi, over 3,000 s and at 33°C. The drug solid-state characteristics, morphology and size distribution were examined before and after processing using X-ray powder diffraction and differential scanning calorimetry, scanning electron microscopy and laser diffraction particle size analysis, respectively. The in vitro dissolution of the treated particles was investigated and compared to that of untreated particles. Results revealed a change in the crystalline structure of carbamazepine with different polymorphs co-existing under various operation conditions. Scanning electron micrographs showed a change in the crystalline habit from the prismatic into bundled whiskers, fibers and filaments. The volume weighted diameter was reduced from 209 to 29 μm. Furthermore, the SAS CO₂ process yielded particles with significantly improved in vitro dissolution. Further research is needed to optimize the operation conditions of the self-built unit to maximize the production yield and produce a uniform polymorphic form of carbamazepine.