Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation.

The aim of this study was to prepare, by melt granulation, granules containing ibuprofen as a poorly water soluble model drug in order to improve its dissolution rate and its availability; lactose as a diluent and poloxamer 188 (Lutrol F68), as a new meltable hydrophilic binder, were used. The granules were prepared in a laboratory-scale high-shear mixer, using a jacket temperature of 50 degrees C and an impeller speed of 500 rpm. The particle size analysis shows that the main fraction was between 200 and 500 microm, while the determination of drug content indicated that ibuprofen was quite uniformly distributed in all the fractions. Scanning Electron Microscopy (SEM), image and fractal analysis revealed that the granules did not have a perfect spherical shape and a rugged surface (D(s)=2.6475). The in vitro dissolution tests showed an increase in the dissolution rate of granules compared to pure drug and physical mixture. The characterisation of the samples, performed by Differential Scanning Calorimetry (DSC) and X-ray powder diffraction (XRD), suggests that the improvement of dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the binder. Stability studies indicated that the granule properties do not change, at least after 1 year of storage at 25 degrees C. In conclusion, the results of this work suggest that the melt granulation technique is an easy and fast method to improve the dissolution rate of ibuprofen, using poloxamer 188 as a new hydrophilic meltable binder.     

Effect of a melt agglomeration process on agglomerates containing solid dispersions

The purpose was to produce solid dispersions of a poorly water-soluble drug, Lu-X, by melt agglomeration in a laboratory scale rotary processor. The effect of binder type and method of manufacturing on the dissolution profile of Lu-X was investigated. Lactose monohydrate and Lu-X were melt agglomerated with Rylo MG12, Gelucire 50/13, PEG 3000, or poloxamer 188. Either a mixture of binder, drug, and excipient was heated to a temperature above the melting point of the binder (melt-in procedure) or a dispersion of drug in molten binder was sprayed on the heated excipient (spray-on procedure). The agglomerates were characterized by DSC, XRPD, SEM, and EDX-SEM. The study showed that the agglomerates containing solid dispersions had improved dissolution rates compared to physical mixtures and pure drug. The melt-in procedure gave a higher dissolution rate than the spray-on procedure with PEG 3000, poloxamer 188, and Gelucire 50/13, whereas the opposite was found with Rylo MG12. This was explained by differences in mechanisms of agglomerate formation and growth, which were dominated by immersion with PEG 3000, poloxamer 188, and Gelucire 50/13, and by distribution and coalescence with Rylo MG12. The spray-on procedure resulted in a higher content of Lu-X in the core of the agglomerates when immersion was the dominating mechanism, and in a higher content in the agglomerate surface when distribution was dominating. The melt-in procedure resulted generally in a homogeneous distribution of Lu-X in the agglomerates. The compounds in the agglomerates were found primarily to be crystalline, and the dissolution profiles were unchanged after 12 weeks storage at 25 degrees C at 50% RH.     

Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique

This work describes a new approach to prepare a fast-release dosage form for carbamazepine (CBZ), involving the use of melt granulation process in high shear mixer for the production of tablets. In particular, the granules containing CBZ were prepared using polyethylene glycol (PEG) 4000 as a melting binder and lactose monohydrate as a hydrophilic filler. The potential of the intragranular addition of crospovidone as a dissolution enhancer and a disintegrant agent was also evaluated. After the analysis of their solid state performed by means of X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC), the granules were characterised from the technological and dissolution point of view. The subsequent step encompassed the preparation and the evaluation of the tablets, including the effect of the extragranular introduction of crospovidone. Besides the remarkable enhancement of drug dissolution rate of the granulates in comparison to physical mixtures and pure drug, no significant differences were found between the dissolution profiles of the granulates containing lactose or crospovidone. However, the difficult disintegration and bad dissolution performance of the tablets not containing intragranular crospovidone highlight the necessity of this disintegrant in the granulating mixture. Moreover, the extragranular addition of a small amount of crospovidone gave rise to a further amelioration of the disintegration and dissolution performances.     

Enhanced Drug Dissolution and Bulk Properties of Solid Dispersions Granulated with a Surface Adsorbent

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug–Gelucire 50/13–Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40°C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent.

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug-Gelucire 50/13-Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40 degrees C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

Effect of hydroxypropylmethylcellulose (HPMC) on the release profiles and bioavailability of a poorly water-soluble drug from tablets prepared using macrogol and HPMC

The aim of the present study was to investigate the effect of hydroxypropylmethylcellulose (HPMC-2208), used as an excipient for controlled release of drug, on the release profiles and bioavailability of the poorly water-soluble nifedipine (NP) from a tablet prepared using macrogol 6000 (PEG) and HPMC. The crushing tolerance of the NP tablet prepared using PEG and HPMC (NP-PEG-HPMC tablet) was markedly increased with increasing compression force used during the preparation from 20 to 200 MPa. The values reached their maximal levels (approximately 13 kg for the NP-PEG-HPMC tablet and 8 kg for the PEG tablet) at the compression force of 100 MPa. Although NP is a poorly water-soluble drug, it was rapidly dissolved from the NP-PEG tablet (without HPMC) due to the improvement of its dissolution rate in the presence of PEG. NP dissolution was complete at the latest within 1 h. On the other hand, dissolution of NP from the NP-PEG-HPMC tablet was significantly delayed with an increase in the concentration of HPMC in the tablet. The dissolution of NP from the NP-PEG-HPMC tablet containing 50% HPMC-2208 was markedly delayed as the viscosity of HPMC also increased. Interestingly, the same peak plasma NP concentration (C(max)) and the area under the plasma NP concentration-time curve (AUC(0-10)) were observed for both the NP-PEG tablet and NP-PEG-HPMC tablets, however, the time to C(max) (t(max)) for the NP-PEG-HPMC tablet was significantly higher when the NP-PEG-HPMC tablet was orally administered to rabbits. We describe here a preparation method of a new sustained-release NP-PEG-HPMC tablet using a mixture of NP-PEG granules (prepared with PEG) and HPMC.     

Evaluation of the composition of the binder bridges in matrix granules prepared with a small-scale high-shear granulator

The aim of this work was to evaluate the binder bridges which can form in hydrophilic matrix granules prepared with a small-scale high-shear granulator. Matrices contained hydroxypropyl methylcellulose (HPMC) as a matrix-forming agent, together with lactose monohydrate and microcrystalline cellulose as filler. Water was used as granulating liquid. A 2(4) full factorial design was used to evaluate the effects of the operational parameters (impeller speed, chopper speed, dosing speed and wet massing time) on the granulation process. The temperature of the sample increased relevantly during the preparation in the small-scale apparatus. The same setup induced different temperature increases for different amounts of powder. This alteration enhances the solubility of lactose and decreases that of HPMC, and thus the quantities of the dissolved components can vary. Accordingly, changes in composition of the binder bridge can occur. Since exact determination of the dissolution of these materials during granulation is difficult, the consequences of the changes in solubility were examined. Differential scanning calorimetry (DSC), thermomechanical analysis (TMA) and X-ray diffraction (XRD) measurements were made to evaluate the films prepared from liquids with different ratios of soluble materials. The DSC and XRD measurements confirmed that the lactose lost its crystalline state in the film. The TMA tests revealed that increase of the quantity of lactose in the film decreased the glass transition temperature of the film; this may be attributed to the interaction of the additives. At a lactose content of 37.5%, a second glass transition appeared. This phenomenon may be indicative of a separate amorphous lactose phase.     

The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.     

A compaction process to enhance dissolution of poorly water-soluble drugs using hydroxypropyl methylcellulose

The purpose of this study was to develop a technique to enhance the dissolution rate of poorly water-soluble drugs with hydroxypropyl methylcellulose (HPMC) without the use of solvent or heat addition. Three poorly water-soluble drugs, naproxen, nifedipine, and carbamazepine, were studied with low-viscosity HPMC USP Type 2208 (K3LV), HPMC USP Type 2910 (E3LV and E5LV), and methylcellulose. Polymer and drug were dry-blended, compressed into slugs on a tablet press or into ribbons on a roller compactor, and then milled into a granular powder. Dissolution testing of the milled powder was performed on USP Apparatus II, 100 rpm, 900 ml deionized water, 37 degrees C. Drug distribution vs. particle size was also studied. The compaction processes enhanced drug dissolution relative to drug alone and also relative to corresponding loosely mixed physical mixtures. The roller compaction and slugging methods produced comparable dissolution enhancement. The mechanism for dissolution enhancement is believed to be a microenvironment HPMC surfactant effect facilitated by keeping the HPMC and drug particles in close proximity during drug dissolution. The compaction methods in this study may provide a lower cost, quicker, readily scalable alternative for formulating poorly water-soluble drugs.     

Preparation and characterization by morphological analysis of diclofenac/PEG 4000 granules obtained using three different techniques

The steam granulation is a new wet granulation technique, which involves the use of steam water instead of traditional liquid water as granulation liquid. The aim of this work was to evaluate the possibility of using this new technique to prepare diclofenac-polyethylene glycol 4000 accelerated-release granules. Steam granules were prepared in a laboratory scale high-shear mixer, and their properties were then compared to those of granules, having the same composition, obtained by traditional granulation techniques (wet and melt granulation). The results showed that, selecting the proper process parameters, it was possible to obtain granules using all the three methods; however, the total process time was significantly shorter for steam granulation (30 min) in comparison to traditional wet granulation (70 min), due to the lower amount of used water. The morphological characterization of steam, water and melt granules, performed by scanning electron microscopy (SEM) and image analysis, revealed that steam granules had a more spherical shape and a larger surface area with respect to water and melt ones, suggesting a possible difference in dissolution behavior. Moreover, differential scanning calorimetry (DSC) and X-ray powder diffraction analysis evidenced the transformation of the drug from its originally crystalline form into the amorphous one. Finally, the in vitro dissolution tests showed an increased dissolution rate of the drug from the granules (in particular steam granules) in comparison to pure drug and physical mixture. In conclusion, the results of this study suggested that the steam granulation technique could be considered an interesting alternative to traditional wet granulation to improve the dissolution rate of diclofenac.     

Drug-fatty acid salt with wax-like properties employed as binder in melt granulation

The tacky and deformable properties of a wax-like drug-fatty acid salt, propranolol oleate (POA), make particle size reduction and separation challenging. The aim of this study was to investigate the use of POA as binder in a melt granulation procedure to improve processing properties. POA is a suitable candidate for binder phase in melt granulation with a melting temperature of 50-56 degrees C. Small batches (ca 30 g) were manufactured using a high shear mixer with lactose monohydrate as the substrate phase. Optimum uniformity of drug content and minimum friability were found at 10% w/w POA binder concentration. POA melt granules exhibited a >10-fold increase in the rate of in vitro dissolution at pH 7.4 with 0.2% w/v sodium lauryl sulphate compared with raw POA. The increased drug surface area in granular form was thought to be responsible for the change in dissolution behaviour. This study has demonstrated that melt granulation using POA as binder is a viable process which leads to beneficial changes in dissolution behaviour for the lipophilic drug-fatty acid salt.     

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with β-cyclodextrin and its derivatives (HP-β-CyD and SBE-β-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride–HP-β-CyD–5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 °C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

Acetazolamide: future perspective in topical glaucoma therapeutics

A 2(4-1) fractional factorial design was used to evaluate the effect of various process variables in fluid bed granulation, on the physico-chemical properties of granule and tablet containing a high dose, poorly water soluble, low density, and micronized drug. The process variables studied were inlet air temperature, inlet air flow, spray rate of the binder solution, and atomization air pressure. Tablets with identical composition, weight, size and hardness were also manufactured in a high shear granulator and their physical properties were determined and compared with those produced by the fluidized bed granulation method. Except for the granule size distribution, other physical properties of granulations and tablets produced in a fluid bed granulator are independent of the selected process variables within the study range. Both atomization air pressure and spray rate of the binder solution had strong impact on granule size distribution. Irrespective of the process conditions used in the fluid bed granulation, granules from this process were more porous, less dense and more compressible than the granules from the high shear granulation process. Comparable tablet dissolution rates to those prepared by the optimized high shear granulation method can be achieved by selecting the appropriate process conditions in fluid bed granulation. These results suggest that wet granulation tablets of a high dose, poorly water soluble, low density, micronized drug can be manufactured using a fluidized bed granulation method, with comparable tablet dissolution rates to those produced with an optimized high shear granulation method.     

Unexpected Performance of Physical Mixtures over Solid Dispersions on the Dissolution Behavior of Benznidazole from Tablets

This work investigated the feasibility of developing benznidazole (BZL) tablets, allowing fast, reproducible, and complete drug dissolution, by compressing BZL-Polyethylene Glycol (PEG) 6000 physical mixtures (PMs) and solid dispersions (SDs). SDs were prepared by the solvent evaporation method at different drug:polymer ratios (w/w). BZL-PEG 6000 formulations were characterized by X-ray diffraction (XRD), scanning electron microscopy, and dissolution studies. The preparation of SD-based BZL tablets by the wet granulation method was carried out and the influence of pregelatinized starch (PS) and starch (S) on the disintegration time and drug dissolution rate was analyzed. SDs showed a significant improvement in the release profile of BZL as compared with the pure drug. As demonstrated by XRD, the crystalline character of BZL remained almost unaltered in both PMs and SDs. BZL release from the PEG 6000 tablets increased by the presence of PS instead S. Unexpectedly, the BZL release from tablets containing PMs was almost equal as compared with the BZL release from tablets containing SDs. In conclusion, the results suggest that PEG 6000 and PS are suitable additives for the development of BZL tablets with enhanced dissolution behavior through the preparation of ordinary PMs, instead the laborious SDs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1016–1023, 2013     

尼美舒利固体分散体的非pH依赖性释放研究

目的以尼美舒利为难溶弱酸性模型药物,研究提高该类药物释放速率的方法。方法以聚乙二醇6000(PEG6000)为载体,采用熔融法制备尼美舒利固体分散体;测定含不同碱化剂(包括NaOH、KOH、Ca(OH)2、Na2CO3、CaCO3)的尼美舒利固体分散体中药物的释放速率。结果加入碱化剂能显著增加尼美舒利在蒸馏水中的释放度,碱化剂不同,药物的释放度不同;碱化剂的碱性越强,分散体的颜色越深,其吸湿性也相对越大。结论在尼美舒利PEG6000固体分散体中加入碱化剂可显著改善该类药物的体外释放特点,并呈现明显的非pH依赖性。     

Influence of binder properties, method of addition, powder type and operating conditions on fluid-bed melt granulation and resulting tablet properties.

The aim of the study was to investigate melt granulation in a laboratory scale fluid-bed granulator with respect to granule growth, granule properties and resulting tablet properties. The parameters investigated were method of addition of PEG (spray-on or addition as flakes), binder concentration, PEG type (3000, 4000 and 6000, sprayed-on), size (PEG 4000, added as three different sized flakes), powder type (two different sized lactose types and corn starch) and operating conditions (volume air flow and heating temperature). Addition of binder as flakes led to layering as a growth mechanism when the size of the flakes was high. Coalescence occurred when the size was low. Coalescence also occurred when spraying was the method of addition. Due to the greater viscosity of the PEG 6000 melt it produced bigger granules than 3000 or 4000. The influence of volume air flow was moderate and the influence of heating temperature in the range of 70-90 degrees C was very low with both methods of addition. The disintegration time of tablets from granules where PEG was added as flakes was shorter than from granules where PEG was sprayed-on. The latter method of binder addition led to tablets which did not disintegrate but eroded. This was apparently caused by formation of a binder matrix, which could not be destroyed by the disintegrant.     

Factors affecting the formation of eutectic solid dispersions and their dissolution behavior

The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers.     

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.     

Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.