Enhanced dissolution rate of celecoxib using PVP and/or HPMC-based solid dispersions prepared by spray drying method

Celecoxib with low solubility and high permeability (BCS class II) in water is a non-steroidal anti-inflammatory drug used in the treatment of pain and inflammation, associated with rheumatoid arthritis, and several other inflammatory disorders. Also, it is a selective cyclooxygenase 2 inhibitor with low water solubility and high crystallinity. The objective of this study was to improve dissolution rate of celecoxib which was water-insoluble drug. Solid dispersions were prepared by spray drying as the solvent evaporation method. The dissolution behavior of solid dispersions was compared with Celebrex^® (Pfizer) as a control group in simulated gastric juice (pH 1.2, 0.5 % SLS. The characterization of the prepared solid dispersions is analyzed by scanning electron microscope, powder X-ray diffractometer, Fourier transform infrared spectroscopy and reverse phase-high performance liquid chromatography The best formulation was SD 8 in this study. It was the cumulative release of 97 % at 120 min. This study suggests that the solubility and bioavailability of poorly water-soluble celecoxib improved through the prepared solid dispersions by spray drying method.     

Controlled and complete release of a model poorly water-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE)(7m)-beta-cyclodextrin as a solubilizing agent.

Sustained-release formulations such as hydroxypropyl methylcellulose (HPMC)-based hydrophilic matrix tablets of poorly water-soluble drugs often result in incomplete release because of the poor solubility and dissolution rate of the drug in the hydrophilic matrix. Sulfobutylether-beta-cyclodextrins ((SBE)(7M)-beta-CDs) have been known to improve the solubility of such drugs by forming inclusion complexes. The present paper deals with the modification of drug release from an HPMC-based matrix tablet of a sparingly water-soluble drug, prednisolone (PDL), using (SBE)(7M)-beta-CD as a solubilizing agent. Tablets were prepared by direct compression of a physically mixed PDL, (SBE)(7M)-beta-CD, and polymer. On exposure to water, an in situ PDL:(SBE)(7M)-beta-CD complex was formed in the gel layer, and enhanced drug release relative to a control formulation was observed (lactose used as the excipient instead of (SBE)(7M)-beta-CD ). Other possible changes due to the incorporation of (SBE)(7M)-beta-CD in the formulation were also probed. Incorporation of (SBE)(7M)-beta-CD lead to a higher water uptake relative to the control (lactose) formulation. For a fixed total tablet weight, polymer type, and loading, the drug release rate appeared to depend on the molar ratio of (SBE)(7M)-beta-CD to PDL and not the absolute amount of (SBE)(7M)-beta-CD present in the matrix tablet. This work shows that incorporation of (SBE)(7M)-beta-CD into the matrix tablets could be considered in designing a sustained-release tablet of poorly water-soluble drugs.     

Gastroretentive Cosolvent-Based In Situ Gel as a Promising Approach for Simultaneous Extended Delivery and Enhanced Bioavailability of Mitiglinide Calcium

Ion cross-linking in situ gels are novel liquid sustained-release drug delivery systems. These systems are unsuitable for poorly water-soluble drugs such as the novel antidiabetic drug mitiglinide calcium (MTG). Thus, our goal was to assess the possibility of using cosolvency approach in formulating gastroretentive in situ gel of the short half-life MTG to simultaneously enhance its bioavailability and sustain its release. MTG in situ gel formulations were developed using propylene glycol as a cosolvent to dissolve MTG in the polymer solution, followed by characterization of viscosity, gel strength, floating ability, and in vitro MTG release and phramacokinetics evaluation. The optimized formulation (composition: 1% gellan gum, 0.75% sodium alginate, 0.75% calcium carbonate, and 7.5% propylene glycol) exhibited reasonable viscosity but on introduction into simulated gastric fluid, it formed firm gel that floated within seconds over the surface and remained buoyant for 24 h. The formula exhibited in vivo sustained release manner of MTG over 24 h and improved the bioavailability of the drug. Thus, cosolvency presents a promising approach to deliver hydrophobic drugs in sustained-release liquid formulations. These formulations will improve diabetic patients' compliance by eliminating the necessity of frequent dosing with a better disease management.     

Effect of biocompatible polymers on the physicochemical and dissolution properties of fenofibrate in nanoparticle system

This study aimed to evaluate the effect of biocompatible polymers on the physicochemical and dissolution properties of poorly water-soluble drugs in nanoparticle systems. Four types of nanoparticles containing poorly water-soluble fenofibrate were prepared using solvent evaporation technique with different biocompatible polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), carbopol and ethylcellulose. Their physicochemical properties were investigated using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The solubility and dissolution of nanoparticle-entrapped fenofibrate were compared with those of free drug powder. Biocompatible polymers affected the morphology and sizes of fenofibrate nanoparticles. PVP or carbopol-based nanoparticles showed spherical appearance, whereas HPMC or ethylcellulose-based nanoparticles formed aggregates with irregular shape. The particle sizes increased in the order of the nanoparticle prepared with carbopol ≤ PVP < HPMC < ethylcellulose. The size of PVP-based nanoparticles did not significantly differ from that of carbopol-based nanoparticles, showing the mean sizes of ca. 10 μm. As compared to free drug powder, the solubility and dissolution of the drug in nanoparticles increased in the order of PVP > HPMC > carbopol > ethylcellulose. The enhanced solubility and dissolution of poorly water-soluble fenofibrate via nanoparticle system did not depend on particle size but on crystallinity. In conclusion, in nanoparticle development of poorly water-soluble drugs such as fenofibrate, the nature of biocompatible polymers plays an important role in the physicochemical and dissolution of poorly water-soluble drugs in the nanoparticles.     

Design and in vitro evaluation of slow-release dosage form of piretanide: utility of beta-cyclodextrin:cellulose derivative combination as a modified-release drug carrier

To modify the release rate of piretanide, a potent loop diuretic, a double-layer tablet was designed, and in vitro release was evaluated. For a rapidly releasing portion, hydrophilic beta-cyclodextrin derivatives were employed to form a water-soluble complex with piretanide. For a sustained-release portion, cellulose derivatives were used to provide appropriate hydrophobicity. The release rate of piretanide in the pH range 1.2-6.8 was automatically monitored by a pH-changeable dissolution testing apparatus. The low solubility of piretanide in acidic medium was significantly improved by complexations with dimethyl-beta-cyclodextrin (DM-beta-CyD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The pH-independent slow release was attained by use of hydroxypropylcellulose (HPC):ethylcellulose (EC) matrices. Then, an optimal formulation of a double-layer tablet was obtained by the combination of each fraction. For example, the tablet consisting of the [DM-beta-CyD/(HPC:EC)] system in the weight ratio [1/3(1:3)] provided a sufficiently slow release of the drug over a period of 8 h in a wide pH region following an initial rapid dissolution.     

Drug/cyclodextrin solid systems in the design of hydrophilic matrices: a strategy to modulate drug delivery rate

The aim of this study was to investigate how the delivery rate of erodible sustained-release hydrophilic matrices intended for the delivery of poorly soluble drugs can be optimized through the incorporation of drug/cyclodextrin binary systems. Carvedilol (CAR), a sparingly water-soluble antihypertensive drug, was selected as a model for the study. As first, we attempted to improve CAR apparent solubility by association with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and then incorporated CAR/HPbetaCD binary systems in sustained-release tablets made of poly(ethyleneoxide) (PEO). Solid CAR/HPbetaCD binary systems were prepared by physical mixing, kneading, co-melting and freeze-drying methods and characterized by DSC and X-ray powder diffractometry. The amount of CAR dissolved from all the HPbetaCD-containing systems was higher than pure CAR, the co-molten and freeze-dried products showing the best dissolution performance. The incorporation of the binary systems in PEO tablets resulted in a CAR release rate much higher than tablets containing only CAR. It was found that the time necessary to achieve complete release from the tablet was linearly related to the dissolution parameters of CAR/HPbetaCD powders. In the case of co-molten and freeze-dried products, all CAR content could be released in about 12 and 10 h, respectively. Our results demonstrate that the incorporation of drug/cyclodextrin solid systems in erodable PEO matrices intended for the delivery of poorly water-soluble drugs is useful to modulate the release rate by controlling the dissolution properties of the drug inside the tablet.     

Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug

Sustained release (SR) tablets containing solid dispersions (SD) granules of a poorly water-soluble drug were prepared to investigate the controlled pH-independent release of the drug. Losartan potassium (LST), an anti-hypertensive agent was chosen as a model drug because of its pH-dependent solubility and short elimination half-life. Poloxamer 188 was used as an SD carrier. A free-flowing SD granule was prepared by adsorbing the melt of the drug and poloxamer 188 onto the surface of an adsorbent, Aerosil 300 (fumed silicon dioxide), followed by direct compression with polyethylene oxide (PEO, 5 × 10(6)) to obtain an SD-loaded SR (SD-SR) matrix tablet. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) revealed partially amorphous structures of the drug in the SD granules. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) images indicated adsorption of SD granules onto the surface of the adsorbent. The SD granules dissolved completely within 10 min, a dissolution rate much higher than that of pure LST. Moreover, pH-independent sustained release of LST from the SD-SR tablet was achieved for 2h in gastric fluid (pH 1.2) and for 10h in intestinal fluid (pH 6.8). A combination of SD techniques using surface adsorption and SR concepts is a promising approach to control the release rate of poorly water-soluble drugs in a pH-independent manner.     

Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble Drugs Prepared by hot-Melt Extrusion

Purpose

Progesterone (PRG) was selected as a model drug to develop a long-acting injection system for poorly water-soluble drugs.

Methods

Microspheres with high density-low porosity were prepared by hot-melt extrusion (HME) combined with wet-milling as the representative formulation, and a microcrystal suspension was also studied as a comparison. The morphology, particle size and distribution, polymorphism, drug distribution, density and porosity were characterized by scanning electron microscopy, laser diffraction particle size analyzer, power X-ray diffraction and DSC respectively. The in vivo performance of the different formulations within 7 days after intramuscular injection was evaluated in male SD rats.

Results

The drug-loading rate of the microspheres could be as high as 40%. The average initial burst release of the microspheres (PLGA lactide:glycolide = 75:25) was only 6.7% much lower than that of the microsuspension (25.7%) and a sustained release was exhibited for at least 7 days. The release mechanism was speculated to be as follows. The microspheres are a drug depot with drug microcrystals in the PLGA matrix which is a layer by layer honeycomb structure.

Conclusions

Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.

     

Osmotic pellet system comprising osmotic core and in-process amorphized drug in polymer-surfactant layer for controlled delivery of poorly water-soluble drug

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodynamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24 h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs.     

Preparation of lovastatin matrix sustained-release pellets by extrusion-spheronization combined with microcrystal dispersion technique

The poorly water-soluble drug lovastatin (LVA) is an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase and has a slow dissolution rate. In this study, a microcrystal dispersion (MCD) technique was used in the preparation of LVA to increase its dissolution rate and then combining with an extrusion-spheronization method, microcrystalline cellulose (MCC) matrix sustained-release pellets containing LVA-MCD were developed and characterized in vitro. Photomicrographs indicated that LVA-MCD existed as fine crystals, of which the mean particle size was reduced from 65.75 μm to 3.97 μm and the dried LVA-MCD powders released completely within 2 hours. SEM results during the release process showed that pellets possessed a matrix structure and after the dissolution test, this matrix structure became loose and porous. The release of LVA was fast and complete, and accumulated release by the optimal formulation was: 0.5 h (20.23 ± 3.40%), 2 h (56.87 ± 2.85%), 4 h (78.71 ± 3.42%), and 8 h (96.81 ± 3.30%). The 3 months accelerating test at 40oC and 75% RH demonstrated that drug release of pellets was not changed and drug degradation was less than 1%. Thus, a novel MCD process with MCC matrix was feasible and effective to get complete release without a lag time for the poorly water soluble drug, LVA, with high stability.     

Novel piroxicam-loaded nanospheres generated by the electrospraying technique: physicochemical characterisation and oral bioavailability evaluation

To determine if a novel electrospraying technique could be applied to an oral drug delivery system for improving the solubility and oral bioavailability of poorly water-soluble piroxicam; the nanospheres were generated with drug and polyvinylpyrrolidone (PVP) using electrospraying technique; and their physicochemical properties, solubility, release and pharmacokinetics were evaluated in comparison with piroxicam powder. All nanospheres had significantly increased drug solubility and dissolution rates in comparison with the drug powder. In particular, the nanosphere composed of piroxicam and PVP at a weight ratio of 2:8 gave about 600-fold higher solubility, 15-fold higher release rate and 3-fold higher AUC in comparison to piroxicam powder, leading to significantly enhanced oral bioavailability in rats, due to the mingled effect of nanonisation along with transformation to the amorphous state. Thus, this electrospraying technique can be utilised to produce a novel oral nanosphere delivery system with enhanced solubility and oral bioavailability for poorly water-soluble piroxicam.     

A nanosystem for water-insoluble drugs prepared by a new technology, nanoparticulation using a solid lipid and supercritical fluid

While the number and diversity of lead compounds has increased with the development of science technologies, ca. 90 % of new chemical entities under development have shown low aqueous solubility, classified as class II or IV of the biopharmaceutics classification system (BCS). The low aqueous solubility hinders their clinical translations due to low bioavailability and dissolution-limited absorption of orally-administered drugs. Several technologies have been employed to improve the solubility of poorly water-soluble drugs. In this paper, a new method of nanoparticulation using fat and a supercritical fluid (NUFS) for the formulation of hydrophobic drugs was applied to solve the low solubility problem. A typical BCS class II drug, itraconazole, was selected and formulated with hydroxypropyl methylcellulose, emulsification, and anticoagulating agents for NUFS. The non-spherical itraconazole nanoparticles prepared by NUFS were ~300–500 nm in size with a ~15-fold improved dissolution rate compared to non-nanoparticles of itraconazole (i.e., raw itraconazole). In addition, a high drug content of ~46 % by weight and a drug loading efficiency greater than 85 % were achieved. Therefore, the new technology for nano-platforms could be a promising solution for solubilization of poorly water-soluble drugs, resulting in improved bioavailability.     

Applicability of (SBE)7m-beta-CD in controlled-porosity osmotic pump tablets (OPTs)

The purpose of this study was to investigate the general application of a controlled-porosity osmotic pump tablet (OPT) utilizing (SBE)7m-beta-CD as both a solubilizer and an osmotic agent for drugs with varying physical properties. OPTs utilizing (SBE)7m-beta-CD were prepared for five poorly soluble and two highly water-soluble drugs. The Japanese Pharmacopoeia dissolution method was used to study the drug and (SBE)7m-beta-CD release from the OPTs. The drug concentration in the OPT core after the OPT was placed in the release medium for two hours was assayed gravimetrically and by HPLC. An appropriate composition ratio (ACR) of (SBE)7m-beta-CD to drug at which drug release from the OPT was complete and pH-independent within the physiological pH range of the GI tract was determined for each drug. The ACR values correlate to the drug concentration in the OPT core when the OPTs were placed in the release medium for two hours. The release profiles of prednisolone (a poorly water-soluble drug) and sodium chloride (a water-soluble compound) from the OPTs were almost the same as that of (SBE)7m-beta-CD. Also, the release rate of each drug per unit membrane surface area from the OPTs was similar, regardless of the differences in drug solubility. The present results confirmed that (SBE)7m-beta-CD serves as both a solubility modulator and as an osmotic pumping agent for OPTs, from which the release rate of both water-soluble and poorly water-soluble drugs can be controlled.     

Improvement of dissolution rate of tacrolimus by solid dispersion technique

Tacrolimus has a poor solubility in water ranging from 4 to 12 μg mL^?1. The mean bioavailability is ~21 %.The present study was carried out with a view to enhance the dissolution rate of poorly water-soluble drug tacrolimus using Gelucire 44/14^® and Gelucire 50/13^® as carriers and lactose monohydrate as an adsorbent. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions (SD) to make final product easy for handling. Phase solubility study was conducted to evaluate the effect of carriers on aqueous solubility of tacrolimus. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as Fickian/anomalous diffusion. All prepared solid dispersions showed dissolution improvement compared to pure drug, with Gelucire 50/13^® as the superior carrier over Gelucire 44/14^®. Almost similar dissolution profile was obtained as a function of storage time; this can be explained by no change in XRD and DSC pattern after 45 days storage period.     

Evaluation of High Molecular Weight Poly(Oxyethylene) (Polyox) Polymer: Studies of Flow Properties and Release Rates of Furosemide and Captopril from Controlled-Release Hard Gelatin Capsules

The powder characteristics and the effect of the molecular weight of polymers as diluents on the release rate of furosemide and captopril from hard gelatin capsules were evaluated. The high molecular weight polymers studied were poly(oxyethylene) homopolymers (Polyox), with molecular weight ranging from 4,000,000 to 7,000,000. Powder characteristics suggested good flowability for these materials and predicted capsule fill weight uniformity. Swelling experiments showed a very high degree of swelling for these materials in both gastric and buffer solution. These polymers can sustain the release rate of both water-soluble and insoluble drugs from drug delivery systems. The low molecular weight polymers have a less pronounced sustained-release effect compared to the high molecular weight polymer material (i.e., those with 7,000,000 molecular weight). An increase in the content of polymer results in a decrease in the release rate of the drug. The solubility of the drugs clearly influenced the release rate. Release kinetics were evaluated and appeared to be influenced by the molecular weight of the polymer, the solubility of drug, and the ratio of the drug to polymer in the capsule. Bimodal release kinetics were exhibited by a number of furosemide formulations (i.e., F5 and F8).     

Preparation and Evaluation of Palm Oil-Based Polyesteramide Solid Dispersion for Obtaining Improved and Targeted Dissolution of Mefenamic Acid

Purpose

The aim of this work was to investigate the functional role of newly synthesised palm oil-based polyesteramide (POPEA) and stearic acid-based polyesteramide (SAPEA) in mefenamic acid (MA) solid dispersion (SD).

Methods

Solid dispersions of MA were prepared by hot melt method, using a combination of POPEA/SAPEA as a polymer carrier. The effects of POPEA/SAPEA mixture ratio, drug loading percentage and influence of different Mw of POPEA (4000–17,000 Da) in SD were investigated. The SDs were characterised for drug content, solubility, dissolution behaviour and physico-chemical characteristics by DSC and FTIR. Comparisons were made with pure drug, physical mixture and a marketed MA formulation.

Results

All SDs demonstrated faster dissolution rate than pure MA and SD 6 formulated with SAPEA/POPEA 4000 Da, 8:2 showed the highest T ₅₀ release rate (45 min) with no significant difference (P?>?0.05) compared to marketed formulation. All SDs showed improved drug release (85.48?±?1.17 to 90.66?±?1.53%) against marketed formulation (81.30?±?1.26%) and MA (56.27?±?1.08%) after 6 h of dissolution. DSC endothermic peak for MA in SD 6 was broadened and shifted to lower temperature (194 °C). FTIR spectroscopy confirmed no chemical changes in MA SD, but establishment of hydrogen bonding between hydroxyl groups of PEA with amine groups of MA was observed by the red shift of OH band in SD samples. The SD was stable (P?>?0.05) at ambient condition for up to 90 days, reflecting by the drug content, dissolution profiles and solubility of the formulation.

Conclusions

POPEA demonstrated surface lowering and wettability effects in improving the aqueous solubility and dissolution rate of MA in SD. The crystalline drug was transformed to amorphous formulation, via solubilisation and crystallisation inhibition effect of the PEA.

     

Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin

Purpose

The introduction of curcumin into clinics is hindered by its low water solubility and poor bioavailability. To overcome these limitations, we developed curcumin implants using poly (??-caprolactone) as the polymeric matrix.

Methods

Implants were prepared by melt-extrusion method; in vitro drug release was optimized for effects of polymer composition, drug load, surface area and water-soluble additives. Implants were also tested under in vivo conditions for cumulative curcumin release, and liver concentration was correlated with its efficacy to modulate selected xenobiotic-metabolizing enzymes (CYP1A1 and GSTM).

Results

Drug release from implants followed biphasic release pattern with Higuchi kinetics and was proportional to the surface area of implants. Drug release increased proportionately from 2 to 10% (w/w) drug load, and incorporation of 10% (w/w) of water-soluble additives (F-68, PEG 8000 and cyclodextrin) did not significantly alter the drug release. In vivo drug release was found to be ??1.8 times higher than in vitro release. Curcumin was detected at 60?±?20 ng/g in the liver after four days of implantation and was almost constant (8?C15 ng/g) for up to 35 days. This time-dependent drop in curcumin level was found to be due to induction of CYP1A1 and GSTM (??) enzymes which led to increased metabolism of curcumin.

Conclusion

Our data showed that these implants were able to release curcumin for long duration and to modulate liver phase I and phase II enzymes, demonstrating curcumin??s biological efficacy delivered via this delivery system.     

复方阿仑膦酸钠缓释片的制备及体外释放度考察

目的:制备复方阿仑膦酸钠缓释片并考察其体外释放度。方法:以羟丙基甲基纤维素(HPMC)、乙基纤维素(EC)、无水乳糖处方用量为因素,体外释放度为指标,用正交试验优化处方,以湿法制粒压片制备制剂,并考察其体外释放度。结果:筛选最优处方为HPMC 80mg、EC 20mg、无水乳糖20mg。所制制剂可持续12h释药,释放行为符合Higuchi方程。结论:所制缓释片的处方合理,具有良好的缓释效果。     

Preparation and characterisation of lornoxicam solid dispersion systems using hot melt extrusion technique

The aim of the research study was to investigate the ability of Soluplus^® and surfactant individually as well as in combination to improve the solubility, subsequently the dissolution profile of lornoxicam (LORX). A laboratory size single screw rotating extruder with temperature and speed control parameters employed during hot melt extrusion (HME) processing of LORX along with polymer-surfactant blends. Soluplus^® used as primary solubilizing agent for preparing solid dispersion (SD). Along with Soluplus^® different concentrations of surfactants such as PEG 400, Lutrol F127, Lutrol F68 were used to solve the permeability issues related to LORX. Encapsulation of LORX particles inside the molten matrix of polymer-excipient blend was confirmed by DSC, XRD and FT-IR. Drug excipient microscopic interaction was further confirmed by scanning electron microscopy (SEM). Depending upon the ratio of the polymer and surfactants used, the solubility of the hot melt extruded LORX was improved and found to be in the range 35–86 μg/ml (actual aqueous solubility of LORX was found to be 0.0083 μg/ml). Dissolution profile of the extruded SD was improved and was found to be in the range of 98–104 % within 20 min (actual dissolution profile of LORX was found to be 8 % at the end of 1 h). SEM and Raman images suggest the formation of amorphous dispersion systems. SD was subjected to stability studies as per ICH guidelines and found to be stable after 6 months when analyzed by HPLC. SD prepared from HME significantly improves the solubility and dissolution profile of LORX—a BCS class II drug.     

Characterisation of the thermal,spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene–polyoxypropylene solid dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F68®), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F68® as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/fluorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F68® up to a concentration of 35% (w/w). Conversely, the solubility in the solid-state matrix was limited to <15% (w/w); determined by Raman spectroscopy, PXRD and fluorescence microscopy. As expected the dissolution properties of MA were significantly influenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was significantly slower. This study has clearly demonstrated the complexity of drug–polymer binary blends and in particular defining the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the significant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4545–4556, 2009