Reduction In Drug Crystallinity Research Articles

Development, Characterization and In Vitro Evaluation of Flurbiprofen Solid Dispersions using Polyethylene Glycols as Carrier

The purpose of the present investigation was to increase the solubility and dissolution rate of flurbiprofen (FLB) by the preparation of its solid dispersion with polyethylene glycol 4000, and 6000 as carriers using solvent evaporation method (SM) and kneading method (KM). Drug polymer interactions were investigated using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), x-ray diffraction (XRD). The prepared solid dispersions were characterized by IR spectroscopy, which suggests no interaction of drug with carriers. XRD and DSC study indicates reduction in drug crystallinity. Drug solubility was more and also the dissolution was rapid for Flurbiprofen solid dispersions compared to pure drug.

Amiodarone hydrochloride: enhancement of solubility and dissolution rate by solid dispersion technique

abstract Amiodarone HCl is an antiarrhythmic agent, which has low aqueous solubility and presents absorption problems. This study aimed to develop inclusion complexes containing hydrophilic carriers PEG 1500, 4000 and 6000 by fusion and kneading methods in order to evaluate the increase in solubility and dissolution rate of amiodarone HCl. The solid dispersion and physical mixtures were characterized by X-ray diffraction, FT-IR spectra, water solubility and dissolution profiles. Both methods and carriers increased the solubility of drug, however PEG 6000 enhanced the drug solubility in solid dispersion better than other carriers. Different media were evaluated for the solubility study, including distilled water, acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 at 37 ºC. Based on the evaluation of the results obtained in the study phase solubility carriers PEG 4000 and PEG 6000 were selected for the preparation of the physical mixture and solid dispersion. All formulations were prepared at drug-carrier ratios of 1:1 to 1:10(w/w). The results of in vitro release studies indicated that the solid dispersion technique by fusion method in proportion of 1:10 (w/w) increased significantly the dissolution rate of the drug. X-ray diffraction studies showed reduced drug crystallinity in the solid dispersions. FT-IR demonstrated interactions between the drug and polymers.

Enhancement of Carvedilol Dissolution; Surface Solid Dispersion Versus Solid Dispersion

The aim of this work was to improve the aqueous solubility of carvedilol (CRV), poorly water soluble drug, using surface solid dispersion (SSD) technique. Drug was deposited over the surface of a hydrophilic, water-insoluble carrier (Avicel pH 101) by solvent evaporation. Pluronic F68 was added as a wetting agent to some formulations. To estimate the effect of SSD technique on drug dissolution, solid dispersions (SDs) of dug and Pluronic F68 were prepared by solvent evaporation. Pluronic F68 was selected due to its inhibiting effect to CYP3A4, an enzyme that contribute to hepatic metabolism of CRV. All formulations were characterized by in vitro dissolution studies; X-ray powder diffraction and scanning electron microscopy. SSD enhanced drug dissolution compared to pure drug. The addition of polymer to drug/carrier composite greatly improved drug dissolution compared to that without the polymer. Compared to SD, SSD showed a better drug release rate. X-ray diffraction indicated the complete reduction in drug crystallinity and the formation of the amorphous form in case of SSD, with limited reduction in crystallinity for SD. The obtained dissolution efficiency of SSD was comparable to that obtained from the marketed CRV product. The study thus presented a system capable of increasing the dissolution rate of CRV with a potential for increased oral bioavailability by inhibiting its pre-systemic metabolism as well.

Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan.

Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan. The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site. Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug-carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug. The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1N HCl showed significant improvement (p<0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199% relative bioavailability with significant improvement (p<0.05) in area under the curve compared to valsartan pure drug. Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.

Self nano-emulsifying drug delivery system for Embelin: Design, characterization and in-vitro studies

CThe objective of the present study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing Capryol-90 as oil phase for the delivery of Embelin, a poorly water soluble herbal active ingredient. Box-Behnken experimental design was employed to optimise the formulation variables, X1 (amount of oil; Capryol 90), X2 (amount of surfactant; Acrysol EL 135) and X3 (amount of co-surfactant; PEG 400). Systems were appraised for visual characteristics for self emulsifying time, globule size and drug release. Optimised liquid formulations were formulated into free flowing granules (S-SNEDDS) by adsorption on the porous materials like Aerosil 200 and Neusilin and thereby compressed into tablet. In vitro dissolution studies of SNEDDS revealed increased in the dissolution rate of the drug. FT-IR data revealed no physicochemical interaction between drug and excipients. Solid state characterization of S-SNEDDS by DSC and Powder XRD confirmed reduction in drug crystallinity which further supports the results of dissolution studies. TEM analysis exhibited spherical globules. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS of Embelin are found to be stable without any significant change in physicochemical properties. Thus, the present studies demonstrated dissolution enhancement potential of porous carrier based S-SNEDDS for poorly water soluble herbal active ingredient, Embelin.

Enhancement of Simvastatin dissolution by surface solid dispersion: effect of carriers and wetting agents

Article history: The aim of this work was to improve the aqueous solubility of simvastatin using the surface solid dispersion (SSD) technique. Water soluble (mannitol and lactose) and insoluble (Avecil PH101) carriers were used. The effect of the addition of polymeric wetting agents (namely PEG6000, Pluronic F68, Myrj 52 and PVP K-30) to drug/carrier composite was also investigated. SSD was prepared by solvent evaporation technique. All formulations were studied regarding the dissolution behavior and solid state characterization (DSC, FT-IR and X- ray diffraction). Both water soluble and insoluble carriers improved dissolution behaviour compared to unprocessed drug, with the former showing the best results. Addition of wetting agent to the water insoluble carrier greatly improved drug dissolution, with PVP K-30 showing better dissolution parameters that was comparable to that of marketed product. Physical state characterization using DSC indicated the marked reduction in drug crystallinity. Xray diffraction confirmed drug amorphousness. The results indicated that SSD may serve as a successful strategy for enhancing solubility of poorly water soluble drugs by proper manipulation of the used additives.

Fabrication and characterization of liquisolid compacts of Embelin for dissolution enhancement

In the present investigation, an attempt was made to improve the dissolution properties of water insoluble herbal active ingredient, Embelin (EBN) by utilizing liquisolid technique, which might offer improved bioavailability. The compacts were prepared using Capryol 90 as non-volatile solvent, Neusilin as carrier and Aerosil 200 as coating material. Mathematical model and 32 factorial design with liquid load factor (X1) and drug concentration (X2) as the independent variables, was utilized to prepare the liquisolid powder systems. The prepared systems were subjected for studying micromeritic properties and possible drug-excipient interactions by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Dissolution studies revealed improvement in the drug release properties. Physicochemical characterization of liquisolid compacts by FTIR, DSC and PXRD techniques suggested reduction in drug crystallinity elaborating for the dissolution enhancement. The study reveals that liquisolid technique is a promising alternative for enhancing dissolution characteristics of EBN.

In vitro and in vivo evaluation of clarithromycin–urea solid dispersions prepared by solvent evaporation, electrospraying and freeze drying methods

Clarithromycin, a poorly water soluble drug, is a new broad spectrum macrolide antibiotic, used in many infections. The objective of the present study was to prepare clarithromycin–urea solid dispersions, with a view to improve the drug dissolution rate and oral bioavailability. The solid dispersions were prepared by solvent evaporation, electrospraying and freeze drying methods in 3 different ratios of drug to urea. Physicochemical properties of the prepared solid dispersions were evaluated as well. Scanning electron microscopic images showed that the microscale size crystals were obtained by freeze drying method. All the solid dispersions showed faster drug release in comparison with pure clarithromycin. Differential scanning calorimetry as well as X-ray powder diffractions showed reduced drug crystallinity in the solid dispersions. Fourier-transform infrared spectroscopy demonstrated hydrogenic bond between NH and CO groups of urea with OH, O and CO groups of clarithromycin. Oral pharmacokinetic studies in the rabbits revealed an improved bioavailability of the solid dispersions in comparison with that of pure clarithromycin powder. Moreover, pharmacokinetic study showed a decrease in inter-individual variation of the oral bioavailability.

Novel Multifunctional Biocompatible Gelatin-Oleic Acid Conjugate: Self-Assembled Nanoparticles for Drug Delivery

In this work, a novel, biocompatible conjugates of gelatin and oleic acid (GOC) were synthesized by a novel aqueous solvent-based method that overcame challenges of completely contrary solubility between gelatin and oleic acid (OA). The GO nanoparticles (GONs) and Paclitaxel encapsulated nanoparticles (PTX-GON) were prepared by self-assembly in water. These nanoparticles (NPs) were then conjugated with folic acid (FA) for targeting cervical cancer cells (Hela cells) and were characterized for their various physicochemical and pharmaceutical properties. Fourier transform infrared spectroscopy (FT-IR) and 1H NMR studies indicated the successful synthesis of GOC which showed low critical aggregation concentration in water (0.015 mg/ml). All NPs were stable in human blood serum and their mean diameters were below 300 nm suitable for passive targeting. Powder X-ray diffraction (PXRD) diffractograms showed the reduction in drug crystallinity and hence, leading to the solubility enhancement of PTX. The release of PTX from both PTX-GON and FA conjugated PTX-GON (PTX-FA-GON) was controlled for a long time. The cytotoxicity results demonstrated great advantages of PTX-FA-GON and PTX-GON over the conventional dosage form of pacliaxel (Taxol). These results, therefore, indicate that GOC is a promising material to prepare drug encapsulated NP as a controlled delivery system and PTX-FA-GON is a potential targeted delivery system for cancer therapy.

IMPROVING THE SOLUBILITY AND DISSOLUTION OF RITONAVIR BY SOLID DISPERSION

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV - infection . One of the major problems with this drug is its low solubility in biological fluids, which results into poor bioavailability after oral administration. Therefore, solid dispersions (SDs) of Ritonavir were prepared using PEG - 4000, PEG - 6000 and PEG - 8000 to increase its aqueous solubility. Ritonavir SDs was prepared in 1:1, 1:2 and 1:4 ratios of the drug to polymer (by weight) by melting method and solvent evaporation method . The prepared solid dispersion was subjected for solubility, drug content, In vitro release and i nfrared (IR) spectroscopic studies, DSC and stability study. In vitro release profiles of all SDs were comparatively evaluated and also studied against pure Ritonavir . Faster dissolution was observed by solid dispersion containing 1:4(P6M4) ratio of drug: PEG - 6000 . The increase in dissolution rate of the drug may be due to increase in wettability , hydrophilic nature of the carrier and due to reduction in drug crystallinity.

Physicochemical characterization of naproxen solid dispersions prepared via spray drying technology

The bioavailability of Naproxen (NPX), a non-steroidal anti-inflammatory drug, is limited after oral administration due to its low solubility in biological fluids. The aims of this study were preparation and characterization of NPX solid dispersions benefitting hydrophilic polymers. Solid dispersions of NPX were prepared at different drug to polymer ratios (1:0.5, 1:1 and 1:2) using crosspovidone and HPMC E4M by means of spray drying method. The dissolution rate of NPX from the solid dispersions, drug/polymer physical mixtures and pure drug was determined at two pH values of 3 and 7.4 simulating gastric and intestinal fluids using USP dissolution apparatus II. The physicochemical properties of the prepared solid dispersions were also characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FT-IR). The dissolution rate of NPX was noticeably increased in the solid dispersions so that almost 90% of drug was released at 60 min while the corresponding value for the physical mixtures and pure drug was revealed to be around 40%. The dissolution rates of the formulations were dependent on the nature and ratio of drug to carriers as well as pH of the medium. DSC and X-ray diffraction displayed reduced drug crystallinity in the solid dispersions. Scanning electron microscopy revealed significant decreased particle size of the drug in the solid dispersions. FT-IR spectroscopy demonstrated no obvious interactions between the drug and polymers.

COMPLEXATION OF NAPROXEN WITH BETA-CYCLODEXTRIN WITH AND WITHOUT POLOXAMER 407 TO ENHANCE DRUG DISSOLUTION

Non steroidal anti-inflammatory drugs (NSAID) have adverse effects on stomach. The histological appearance of affected mucosal cells ranging from mild to sever inflammation. Accordingly, the purpose of this study was to investigate the effects of: (i) s-cyclodextrin (s- CD), Poloxamer-407 (PLX) and sorbitol (Sorb) as carriers and (ii) freeze drying and physical mixing as techniques on solubility and dissolution of a model poorly water soluble NSAID drug, Naproxen (Nap) for the ultimate aim to avoid gastric discomfort via enhancement drug release. Therefore, two binary drug/carrier (1:1 and 1:4 w/w Nap/carrier ratios) combinations were prepared. The effect of multicomponent carrier systems, using ternary physical mixtures of Nap with s-CD and PLX on the drug solubility and dissolution were also studied. All formulations were characterized using solubility, content uniformity, dissolution studies, Fourier transform infra-red (FT-IR) spectroscopy, and differential scanning calorimetry (DSC). All tested Nap/ combinations showed enhancement in drug release compared to pure drug, except Sorb that show a slight improvement only at high sugar concentration. Ternary Nap combinations showed the highest improvement of drug dissolution, compared to binary ones. Freeze dried formulations showed a marked enhancement in drug release especially in the first few minutes, compared to physical mixtures. Thermal studies indicated a reduction in drug crystallinity with freeze dried samples giving a higher amorphous yield obtained compared to binary physical mixtures.

Enhancement of dissolution of Telmisartan through use of solid dispersion technique surface solid dispersion

The present study was aimed to increase the solubility of the poorly water soluble drug Telmisartan by using Surface solid dispersion (SSD) made of polymers like Poloxamer 407, PEG 6000 by Solvent evaporation method. The drug was solubilized by surfactants and/or polymers then adsorbed onto the surface of extremely fine carriers to increase its surface area and to form the SSD which give the more Surface area for absorption of the drug. A 22 full factorial design was used to investigate for each carrier the joint influence of formulation variables: Amount of carrier and adsorbent. Saturation solubility studies shows the improvement in solubility of drug batch SSD 8 give more solubility improvement than the other batch, in-vitro dissolution of pure drug, physical mixtures and SSDs were carried out in that SSDs were found to be effective in increasing the dissolution rate of Telmisartan in form of SSD when compared to pure drug. Also FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry studies were carried out in order to characterize the drug and Surface solid dispersion. Furthermore, both DSC and X-ray diffraction showed a decrease in the melting enthalpy and reduced drug crystallinity consequently in SSDs. However, infrared spectroscopy revealed no drug interactions with the carriers.

Formulation and physicochemical characterization of chitosan/Acyclovir co-crystals

In the current study, the influence of chitosan on the dissolution rate and bioavailability of acyclovir has been illustrated through the preparation of co-crystals by simple solvent change method. Chitosan was precipitated on acyclovir crystals using sodium citrate as the salting out agent. The pure drug and the prepared co-crystals using different concentrations and molecular weights of chitosan were characterized in terms of drug content, particle size, thermal behavior, IR analysis, surface morphology, in vitro drug release and physical stability. The results obtained showed that the practical yield of the prepared co-crystals was found to be inversely proportional to chitosan concentration. The drug content of the co-crystals was uniform among the different batches. The prepared co-crystals showed a slower drug release when compared to that of pure drug. The considerable change in the dissolution rate of acyclovir from optimized crystal formulation was attributed to the wetting effect of chitosan, the reduction in drug crystallinity and the altered surface morphology. The thermograms showed a decrease in the melting enthalpy of acyclovir indicating a disorder in the crystalline content whereas IR spectroscopy studies revealed an interaction between acyclovir and chitosan. The optimized co-crystals were stable for three months at 40°C and 75 ± 5% RH.

Physicochemical and anti-bacterial performance characterization of clarithromycin nanoparticles as colloidal drug delivery system

The objective of the present study was to prepare clarithromycin (CLR) loaded biodegradable nanoparticles (NPS), with a view to investigate its physicochemical properties and anti-bacterial activity. PLGA was used as a biodegradable polymer and the particles were prepared by nano-precipitation method in 3 different drugs to polymer ratios. Evaluation of the physicochemical properties of the prepared nanoparticles was performed using encapsulation efficiency, nanoparticle production yield, dissolution studies, particle size analysis, zeta potential determination, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffractometry. The antimicrobial activity against Staphylococcus aureus was determined using serial dilution technique to achieve the minimum inhibitory concentration (MIC) of NPs. The particles were between 189 and 280 nm in size with narrow size distribution, spherical shape and 57.4-80.2% entrapment efficiency. Zeta potential of the NPs was fairly negative. The DSC thermograms and X-ray diffraction patterns revealed reduced drug crystallinity in the NPs. FT-IR spectroscopy demonstrated possible noncovalent interactions between the drug and polymer. In vitro release study showed an initial burst followed by a plateau during a period of 24h. The NPs were more effective than intact CLR against S. aureus so that the former showed equal antibacterial effect at 1/8 concentration of the intact drug. In conclusion, the prepared CLR nanoparticles are more potent against S. aureus with improved MICs and appropriate physicochemical properties that may be useful for other susceptible microorganisms and could be an appropriate candidate for intravenous, ocular and oral and topical preparations.

Preparation, Characterization, and In Vitro Evaluation of Ezetimibe Binary Solid Dispersions with Poloxamer 407 and PVP K30

Ezetimibe (EZE), a water insoluble drug, depicts variable bioavailability. The objective of the present investigation was to improve dissolution characteristics of EZE, which might offer improved bioavailability. The solid dispersions were prepared using poloxamer 407 (L 127) and polyvinyl pyrrolidone by melt and solvent method, respectively. Phase solubility studies indicated linear relationship between drug solubility and carrier concentration. In vitro release studies revealed improvement in the dissolution characteristics of EZE in solid dispersions. Solid dispersion with L 127 gave better rate and extent of dissolution. The best fit model indicating the probable mechanism of drug release from solid dispersions was found to be Korsemeyer–Peppas. The results of characterization of solid dispersions by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction revealed reduction in drug crystallinity which might be responsible for improved dissolution properties. The tablets of solid dispersion, containing L 127 prepared by direct compression, exhibited better drug release as compared to marketed formulation.

Studies in Dissolution Enhancement of Ezetimibe by Solid Dispersions in Combination with a Surface Adsorbent

The aim of this investigation was to improve the dissolution properties of the water-insoluble drug ezetimibe (EZE) and potentially improve bioavailability. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions. PEG 4000, PEG 6000, and Gelucire 44/14 were used as hydrophilic carriers, and lactose monohydrate was used as an adsorbent. Phase solubility curves are of AL type, indicating a linear relationship between drug solubility and carrier concentration. Dissolution studies reveal an improvement of in vitro drug release. Mathematical modeling indicates that drug release data are best described by the Korsmeyer–Peppas model, with Fickian diffusion as the possible drug-release mechanism. Physicochemical characterization of solid dispersions by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) suggests a reduction in drug crystallinity following dissolution enhancement. Hence, the present investigation reveals that the dissolution characteristics of EZE could be ameliorated in a solid dispersion. INTRODUCTION Out of several methods employed to enhance the dissolution characteristics of poorly water-soluble drugs, solid dispersion techniques have been widely reported by various researchers with encouraging results for different drugs. However, a solid dispersion system is somewhat limited by poor flow properties and poor stability. The processing variables of solid dispersions can be improved by the addition of adsorbent in the solid dispersion melt, thereby increasing the effective surface area of the drug leading to improved dissolution (1, 2). Various carriers have been used to prepare solid dispersion systems; among those, polyethylene glycols (PEG) and Gelucire 44/14 are employed in the present investigation. PEGs are used because of their low toxicity, high water solubility, low cost, and availability in a wide range of molecular weights. Gelucire 44/14 is a mixture of glycerol and PEG 1500 esters of long-chain fatty acids. The suffixes 44 and 14 refer to its melting point and its hydrophilic/lipophilic balance (HLB), respectively. PEG 4000, PEG 6000, and Gelucire 44/14 have been used successfully to improve the dissolution properties of poorly water-soluble drugs by preparing solid-dispersion systems (3–5). However, the solid dispersions prepared with these carriers are sticky and difficult to handle. Hence, they must be used in amalgamation with an adsorbent to improve their flow properties. Ezetimibe (EZE), 1-(4–fluorophenyl) –3(R)-[3-(4–fluorophenyl) –3(S) hydroxy-propyl]-4(S)-(4-hydroxyphenyl)-2azetidinone, is the first lipid-lowering drug that inhibits the intestinal uptake of cholesterol without affecting the absorption of fat-soluble nutrients. It is indicated as a monotherapy or in combination with statins for the treatment of hypercholesterolemia (6). EZE, being practically insoluble in water, exhibits a low dissolution profile in gastrointestinal fluids with variable bioavailability. Thus, researchers have investigated different approaches to ameliorate the dissolution characteristics of EZE (7–9) and optimize bioavailability with a less variable pharmacokinetic profile. In the present investigation, an attempt was made to improve the dissolution properties of EZE by preparing free-flowing solid dispersions. A combination of solid dispersion and adsorption techniques was employed for the preparation of the solid systems, using lactose monohydrate as adsorbent. The prepared solid dispersions were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). MATERIALS AND METHODS Materials EZE was kindly gifted by Mepro Pharmaceuticals Ltd. (Surendranagar, India). Gelucire 44/14 was a generous gift sample from Gattefosse Pvt. Ltd. (Mumbai, India). PEG 4000 and PEG 6000 were purchased from Sisco Research Lab Pvt. Ltd. (Mumbai, India). All reagents were of analytical grade. Double-distilled water was used throughout the work. Methods Phase Solubility Phase solubility studies were carried out as described by Higuchi and Connors (10). A quantity of EZE (about 10 mg) that exceeded its solubility was added to flasks containing 25 mL of solutions of different polymer *Corresponding author. diss-18-03-07.indd 55 8/31/2011 3:26:40 PM dx.doi.org/10.14227/DT180311P55

Enhanced Dissolution and Bioavailability of Raloxifene Hydrochloride by Co-grinding with Different Superdisintegrants

The present study investigated the effect of co-grinding raloxifene HCL (RHCL) with different superdisintegrants, namely crospovidone (CP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), using a ball mill, in order to determine the potential effect on dissolution rate and bioavailability of raloxifene hydrochloride (RHCL). The dissolution studies of the co-ground compositions and the corresponding physical mixtures were carried out in U.S. Pharmacopeia (USP) Type II apparatus. The solid state interactions of the co-ground and the physical mixtures were evaluated by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The pharmacokinetics of co-ground mixture (1 : 5 RHCL : CP) and milled RHCL was evaluated following oral administration (25 mg/kg) in healthy female Sprague-Dawley rats. DSC studies showed that the crystalline nature of RHCL was reduced after co-grinding with superdisintegrants, while co-grinding with CP resulted in significant particle-size reduction of the mixture. Significant enhancement in dissolution rate was observed with co-ground mixture of RHCL with CP (1 : 5). The extent of the mean plasma exposures of RHCL was 7-fold higher in animals treated with co-ground mixture of RHCL, CP (1 : 5) compared to animals treated with milled RHCL. Co-grinding of RHCL with CP, reduced drug crystallinity, increased the rate and extent of dissolution, and improved bioavailability.

Cogrinding as an approach to enhance dissolution rate of a poorly water-soluble drug (gliclazide)

Gliclazide is practically insoluble in water. In order to improve the drug dissolution rate, cogrinding method was used as an approach to prepare gliclazide coground/solid dispersions (SDs) in the carriers such as povidone (PVP-K30), crospovidone and microcrystalline cellulose (Avicel PH 101) with different drug to carrier ratios. The dissolution rate of gliclazide from the SDs was measured at two physiological pH values of 1.2 and 7.2 simulating gastric and intestinal fluids using USP dissolution apparatus II. The concentration of the dissolved drug in the medium was determined by direct or first-derivative UV spectroscopy. The dissolution rates of the formulations were dependent on the nature and ratio of drug to carriers in SDs and the corresponding physical mixtures as well as the pH of the medium. At a higher pH the drug has a faster dissolution than at a lower pH. The fastest dissolution rates were observed from coground formulations with the drug to carrier ratio of 1:5. The amount of drug dissolved in 15 min from these SDs was varied from 96% in the case of Avicel SD to 100% for SD of PVP. Whereas the amount of drug released in the same time from unground drug powder (UD), ground drug powder (GD) and all physical mixtures was between 60 and 80%. These results indicate that the dissolution rate is highly enhanced from the SDs. DSC as well as X-ray diffraction showed reduced drug crystallinity in SDs. Scanning electron microscopy and particle size analysis revealed significant decreased particle size of the drug in SDs. FT-IR spectroscopy demonstrated no detectable interactions between the drug and carriers. In addition to latter evidence, increased wettability and hydrophilicity of drug particles and deaggregation brought about by the carriers are the reasons for enhanced drug dissolution from the SDs. One of the possible advantages of formulating an insoluble drug such as gliclazide is that if it is used in preparation of capsules or tablets of the drug, its dose might be reduced which is economically beneficial.

Inclusion complexes of lamotrigine and hydroxy propyl β-cyclodextrin: solid state characterization and dissolution studies

Lamotrigine (LMN) is an antiepileptic drug, with poor aqueous solubility, which might lead to erratic bioavailability. The objective of the present work was to improve the dissolution characteristics of the LMN using Hydroxy propyl β-cyclodextrin (HP β-CD), which might offer reliable bioavailability. The phase solubility profile was classified as AL-type, revealing 1:1 stoichiometric complexation, with a stability constant (Ks) of 573 M−1. Binary systems of LMN and HP β-CD were prepared in different molar ratios (1:1, 1:2, 1:3 and 1:4) by kneading method. The binary systems were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction Analysis (PXRD). Results revealed that in the kneaded products the entire drug was entrapped inside the HP β-CD cavity and reduction in drug crystallinity also took place, which may be responsible for improved dissolution characteristics as compared to that of the pure drug as depicted from the dissolution studies.