Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

In Vitro Characterization of a Novel Polymeric System for Preparation of Amorphous Solid Drug Dispersions

Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP–HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (T _g) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP–HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties.     

Investigation of Ethylene Oxide-co-propylene Oxide for Dissolution Enhancement of Hot-Melt Extruded Solid Dispersions

The optimal design of amorphous solid dispersion formulations requires the use of excipients to maintain supersaturation and improve physical stability to ensure shelf-life stability and better absorption during intestinal transit, respectively. Blends of excipients (surfactants and polymers) are often used within pharmaceutical products to improve the oral delivery of Biopharmaceutical Classification System class II drugs. Therefore, in this study, a dissolution enhancer, poloxamer 407 (P407), was investigated to determine its effect on the dissolution properties and on the amorphous nature of the active pharmaceutical ingredient contained in the formulation. Phase solubility studies of indomethacin (INM) in aqueous solutions of P407 and poly(vinylpyrrolidone-vinyl acetate copolymer) showed an increase in the kinetic solubility of INM compared with the pure drug at 37°C with a K_a value of 0.041 μg/mL. The solid dispersions showed a higher dissolution rate when compared to pure and amorphous drugs when performed in pH buffer 1.2 with a kinetic solubility of 21 μg/mL. The stability data showed that the amorphous drug in solid solutions with poly(vinylpyrrolidone-vinyl acetate copolymer) and P407 remained amorphous, and the %P407 loading had no effect on the amorphous stability of INM. This study concluded that the amorphous solid dispersion contributed to the increased solubility of INM.     

Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration

The objectives of this study were to formulate and stabilize amorphous formulation of low T(g) drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies. The formation of single-phase amorphous form was confirmed by DSC and PXRD. The melt extrudates showed a higher intrinsic dissolution rate (IDR), and solubility compared to the pure drug. The amorphous drug in solid solutions with EPO, PVP-VA, and PVPK30 showed tendency to revert back to crystalline form. However, the rate of reversion was dependent on the nature and concentration of the polymer. The solid solution with high ratio of EPO provided superior stabilization of the amorphous INM from crystallization. The stability of the amorphous form of INM could not be related to the glass transition temperature of the formulation as the mechanism of stabilization with EPO appears to be molecular interaction rather than immobilization. The presence of specific molecular interactions between INM and EPO was also shown by the antiplasticization effect.     

Enhanced solubility and oral bioavailability of itraconazole by combining membrane emulsification and spray drying technique

The objective of the present study was to enhance solubility and bioavailability of itraconazole by a combined use of membrane emulsification and spray drying solidification technique. A shirasu-porous-glass (SPG) membrane with a mean pore size of 2.5 μm was used to produce monodispersed microemulsions of itraconazole consisting of methylene chloride as the dispersed phase, a mixture of Transcutol HP and Span 20 as a stabilizer, and dextran as solid carrier dissolved in water as the continuous phase. The dispersed phase permeated through the SPG membrane into the continuous phase at an agitator speed of 150 rpm, a feed pressure of 15 kPa and a continuous phase temperature of 25°C and the resultant emulsion was solidified using spray-drying technique. Solid state characterizations of the solid emulsion showed that the crystal state of itraconazole in solid emulsion was converted from crystalline to amorphous form. The solid emulsion of itraconazole displayed a significant increase in the dissolution rate than that of pure itraconazole. Furthermore, the solid emulsion after oral administration gave about eight-fold higher AUC and about ten-fold higher C(max) in rats than pure itraconazole powder (p<0.05), indicating this formulation greatly improved the oral bioavailability of drug in rats. Thus, these results demonstrated that the SPG membrane emulsification system combined with spray-drying technique could be used as a promising technique to develop solid formulation of itraconazole with enhanced solubility and bioavailability.     

Possibilities and Limiting Factors for the Use of Dissolution as a Quality Control Tool to Detect Presence of Crystallinity for Amorphous Solid Dispersions: An Experimental and Modeling Investigation

In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation. The experiment shows that under ideal nonsink conditions with respect to crystalline solubility, dissolution can indeed be predictive of crystallinity in the formulation. However, the limit of detection for crystallinity with quality control dissolution can change based on inherent variabilities in the drug product. In addition, it is demonstrated that the method's sensitivity and accuracy might be reduced if the crystalline particles are sufficiently small with respect to the solid dispersion particles. To further demonstrate the limits of the dissolution method, a dissolution model was also explored to simulate and predict the sensitivity of the dissolution response toward crystallinity based on solubility in the media and particle size of the crystals.     

Preparation, characterization and in vitro dissolution studies of solid dispersion of meloxicam with PEG 6000

The poor solubility and wettability of meloxicam leads to poor dissolution and hence showing variations in bioavailability. The present study is aimed to increase solubility and dissolution of the drug using solid dispersion techniques. The solid binary systems were prepared at various drug concentrations (5-40%) with polyethylene glycol 6000 by different techniques (physical mixing, solvent evaporation). The formulations were characterized by solubility studies, differential scanning calorimetry, fourier transform infrared spectroscopy and in vitro dissolution rate studies. The solubility of drug increased linearly with increase in polymer concentration showing A(L) type solubility diagrams. Infrared spectroscopy studies indicated the possibility of hydrogen bonding with polymer. The differential scanning calorimetry and powder X ray diffraction demonstrated the presence of polymer as eutectica or monotectica in solid dispersion along with the physical characteristics of the drug (crystalline, amorphous or a mixture of both). The solid dispersions of the drug demonstrated higher drug dissolution rates than physical mixtures and pure meloxicam, as a result of increased wettability and dispersibility of drug in a solid dispersion system.     

Solubility enhancement and physicochemical characterization of carvedilol solid dispersion with Gelucire 50/13

The objective of the study was enhancement of dissolution of poorly soluble carvedilol by solid dispersions (SDs) with Gelucire 50/13 using solvent evaporation method. The solubility of carvedilol showed linear increase with increasing concentrations of Gelucire indicating A_L type solubility diagrams. SDs characterized for physicochemical characteristics using differential scanning calorimetry and X-ray diffractometry revealed transformation of crystalline form of drug to amorphous form which was confirmed by scanning electron micrographs. Further fourier transform infrared spectroscopy results suggested there is no drug carrier interaction. From the dissolution parameters such as mean dissolution time, dissolution efficiency and drug release rate, improved dissolution characteristics for SDs were observed compared with physical mixture and pure drug. Thus SDs of carvedilol in Gelucire 50/13 showed enhanced solubility and dissolution rate compared to pure drug.     

Review of solubilization techniques for a poorly water-soluble drug: carbamazepine

Solubility behavior of drugs remains one of the most challenging aspects in formulation development. With the introduction of various solubility improvement techniques it should be possible to overcome solubility-linked issues. Several years of research and various novel techniques for improvement of drug solubility have resulted in only a few marketed products. There are various techniques that were studied in depth to improve carbamazepine (CBZ) solubility. Several in vitro and in vivo studies have shown significant improvement in dissolution and bioavailability of CBZ. This article begins with an overview of the historical background and definitions of the various techniques, including the novel ones. The second part of the article is devoted to the techniques, materials used, procedures, and characterization of various developed formulations. The current review is further extended specifically to drug dissolution in relation to drug crystalline in various solubilization approaches.     

Characterization and in vitro dissolution behaviour of ketoconazole/β- and 2-hydroxypropyl-β-cyclodextrin inclusion compounds

The effect of β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin on the solubility of ketoconazole in different media were studied. A type A_L solubility diagram was obtained for ketoconazole and the two cyclodextrins in buffer solution, pH 5 and pH 6. The stability constants between ketoconazole and the two cyclodextrins were calculated from the phase solubility diagrams. Increased ionization of the imidazole derivative decreased the values of the stability constants. The formation of solid inclusion complexes were experimentally prepared by the kneading and spray-drying techniques. In order to confirm solid complex formation, X-ray diffractometry and differential scanning calorimetry were used. It was found that the spray-drying technique could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of ketoconazole from the inclusion complex made by spray-drying were faster than the pure drug, kneading systems and the physical mixtures of drug and cyclodextrins. The enhanced dissolution rate of spray-dried products might be attributed to the decreased particle size, the high-energetic amorphous state and inclusion complex formation.     

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.

     

Detecting Crystallinity in Amorphous Solid Dispersions Using Dissolution Testing: Considerations on Properties of Drug Substance,Drug Product,and Selection of Dissolution Media

Dissolution testing has long been used to monitor product quality. Its role in quality control of amorphous solid dispersion (ASD) formulations is relatively new. In the presence of the crystalline phase, the dissolution of ASDs is determined by the dynamics between the dissolution rate of the amorphous solids and the rate of crystal growth. The detection of crystalline phase by dissolution test has not been well understood in the context of drug properties, formulation characteristics and dissolution test variables. This study systematically evaluated the impact of key parameters such as intrinsic crystallization tendency of the API, drug loading, extent of dissolution sink conditions and level of crystallinity on the ASD dissolution behavior. The results indicated diverse dissolution behaviors due to the differences in the intrinsic crystallization propensity of the drug, the drug loading, the ASD polymers and the dissolution sink index. Each of the complex dissolution profiles were interpreted based on visual observations during dissolution, the appropriate sink index based on the amorphous solubility, and the competition between drug dissolution versus crystallization. The findings of this study provide insights towards the various considerations that should be taken into account towards rationally developing a discriminatory dissolution method.     

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.     

The Effect of Carrier-Drug Ratios on Dissolution Performances of Poorly Soluble Drug in Crystalline Solid Dispersion System

The choice of carrier and drug ratio are critical factors as far as the type of solid dispersion is concerned. Amorphous solid dispersion has been cited as the most desirable type among the different types of solid dispersion due to the benefit of amorphicity in increasing the drug solubility of a poorly soluble drug. Recent reports delineated that a partially crystalline solid dispersion system may perform better due to the inherent issue of solution mediated recrystallisation of a completely amorphous system. In oppose to the conventional choice of using amorphous polymer, this study aimed to investigate the use of a crystalline carrier, polyethylene glycol (PEG) for dissolution enhancement of a model poorly soluble drug, Flurbiprofen (FBP), a BCS Class II candidate. Solid dispersions of different FBP to PEG 6000 molar ratios via solvent evaporation were prepared. Physical characterisation of preparations was performed using differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and optical microscope. DSC and ATR-FTIR analyses suggest the obtained solid dispersion exhibits crystalline FBP. This is then supported by the optical microscope analysis as the birefringence of crystals was noted. Further increasing the drug-carrier molar ratio to one-to-three and one-to-six showed that there was an amorphous FBP constituent in the system. DSC analysis revealed the melting point depression of FBP by the carrier which signifies interaction between the drug and polymer. Dissolution study showed the solid dispersion of FBP improves the drug solubility and drug release compared to the pure drug. A higher carrier ratio in the formulation results in a higher drug release.     

Aminoalkyl methacrylate copolymers for improving the solubility of tacrolimus. I: Evaluation of solid dispersion formulations

The aim of this study was to investigate the effect of Eudragit E/HCl (E-SD) on the reprecipitation of a poorly water-soluble drug, tacrolimus. To evaluate the inhibition of reprecipitation of E-SD, reprecipitation studies on tacrolimus were conducted using a dissolution test method. Solubility of tacrolimus was measured at regular intervals in a dissolution media, in which tacrolimus was dissolved in ethanol, and the test media contained additives for inhibiting precipitation. Supersaturation profiles of tacrolimus were observed, and were maintained for 24h only with E-SD. Solid dispersion formulations of tacrolimus prepared with hydroxypropylmethylcellulose (HPMC) or E-SD in different drug/carrier ratios were also investigated. Solid dispersions prepared with E-SD showed higher solubility of tacrolimus compared with that of HPMC. In the E-SD formulation, the drug solubility influences to drug/carrier ratio. The formulation of drug/E-SD (1/5) showed the highest drug solubility. Thus, it may be inferred that a definite drug/carrier ratio exists to increase drug solubility. Further, by mixing E-SD the solid dispersion prepared with HPMC showed enhanced drug solubility.     

Formulation of highly purified fenugreek gum based silica lipid drug delivery system for simvastatin with enhanced dissolution rate and in vitro characterization

In current study, highly purified fenugreek gum (HPFG) isolated by patented method explored as emulsifier and hydrophilic solid carrier in drug delivery system. Anti-hyperlipidemic drug simvastatin (SIM) was selected as drug model for the study as it is associated with poorly water solubility and low bioavailability problems (<5 %). A suitable HPFG-based silica lipid system composed of SIM (1.5 %), medium chain triglyceride Capmul^® MCM (10 %) as lipid phase, 0.6 % HPFG as emulsifier and HPFG 2.5 %, different grades colloidal silica (7.5 %) (Aerosil^® 300 Pharma, Aerosil^® 380 Pharma and Aeroperl^® 300 Pharma) as hydrophilic solid carriers was developed. The optimized HPFG-based silica lipid systems were characterized for physical characteristics like flow ability, compressibility, redispersiblity, solubility and in vitro drug release using USP apparatus II in pH 6.8 phosphate buffer. The system was also characterized for Fourier transform infrared spectroscopy, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The developed formulation was found to have excellent flow property, readily redispersiblity, better aqueous solubility and showed 3–4-fold increase in dissolution rate as compared to plain drug and marketed formulation (Simlo^® 10). Transition of crystalline drug to amorphous state was confirmed by DSC, PXRD and SEM studies. Enhanced dissolution rate and solubility possibly attributed to improved wetting, amorphous drug state and facilitated diffusion from lipid-based system. Thus developed HPFG-based silica lipid system provides an alternative means for SIM with enhanced dissolution rate and stability in oral solid dosage form.     

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin–arginine

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin–arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin–arginine (SD IND–ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined. Dissolution profiles of tablets with SD IND–ARG (TAB SD IND–ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND–ARG) and to the dissolution of pure spray dried powder.Concerning tableting, the developed formulation allowed for the preparation of tablets with a broad range of compaction pressures resulting in different porosities and tensile strengths. XRPD results showed that, overall, no crystallization occurred neither during tableting nor during long-term storage. Dissolution profiles of TAB SD IND–ARG showed an immediate release of IND by erosion. The solubility of crystalline IND was exceeded by a factor of about 4, which was accompanied by a slow crystallization. For TAB PM IND–ARG, an in situ amorphization of IND in the presence of ARG was observed. As a result, a supersaturation was obtained, too, followed by a faster crystallization compared to TAB SD IND–ARG. In conclusion, the AUC_24h of TAB SD IND–ARG was twofold higher than the AUC_24h of TAB PM IND–ARG. Interestingly, different plateaus were obtained for TAB SD IND–ARG, TAB PM IND–ARG and pure SD IND–ARG after 24 h dissolution, which could be explained by the formation of different polymorphic forms of indomethacin.     

Drug Resinates an Attractive Approach of Solubility Enhancement of Atorvastatin Calcium

A substantial number of new chemical entities and marketed drugs show poor solubility characteristics and amorphisation is one of the favorable approaches to enhance solubility characteristics of such poorly soluble drugs. Formulation efforts in the present study were devoted to investigate amorphisation of a model poorly soluble drug, atorvastatin calcium by molecular complexation with anion exchange resin, Duolite^®AP 143/1093 and hence enhancement in its solubility characteristics. Drug resinates in 1:1, 1:2, and 1:4 weight ratios were prepared by simple batch operation and subsequently studied for drug content, residual solvent content, molecular interactions, solid state characterisation and solubility characteristics. During initial characterisation, all the proportions of drug resinates, except 1:1 proportion showed partial amorphisation of the drug, whereas 1:1 proportion showed complete amorphisation of the drug. This proportion reported distinctly enhanced solubility characteristics over pure drug and other proportions. Such amorphisation and solubility enhancement could be attributed to the binding of individual drug molecules to the functional sites of the resin molecules, either partially or completely, resulting in reduction of crystal lattice energy, a main barrier to dissolution. Hydrophilic nature of ion exchange resin matrices also assisted in enhancing dissolution of the drug from the resinates. During accelerated stability study, there was an insignificant decrease in solubility characteristics of the drug and its amorphous form was also found to be stable in 1:1 proportion. Atorvastatin resinates formed in 1:1 weight ratio were in stoichiometric proportion and such drug resinates in stoichiometric proportion showed to have tremendous potential in conversion of crystalline form of drug substances to its amorphous form and subsequent stabilisation. It hence proved to be a very effective, yet simple approach for improving solubility characteristics of poorly soluble actives.     

Statistical modeling,optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment

Objective: Lopinavir (LPV), an antiretroviral protease inhibitor shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism. The aim of the present work was to investigate the potential of the solid self-nanoemulsifying drug delivery system (S-SNEDDS) in improving dissolution rate and oral bioavailability of LPV.

Materials and methods: Liquid SNEDDS (L-SNEDDS) of LPV were prepared using Capmul MCM C8, Cremophor RH 40 and propylene glycol and their amounts were optimized by Scheffe’s mixture design. L-SNEDDS formulations were evaluated for different physicochemical and in vitro drug release parameters. S-SNEDDS were prepared by adsorbing L-SNEDDS on Neusilin US2 and characterized for solid-state properties. In vivo bioavailability of S-SNEDDS, marketed Lopinavir?+?Ritonavir (LPV/RTV) formulation and pure LPV was studied in Wistar rats. Stability study of S-SNEDDS was performed as per ICH guidelines.

Results and discussion: Optimized L-SNEDDS obtained by Scheffe design had drug loading 160?±?1.15?mg, globule size 32.9?±?1.45?nm and drug release?>95% within 15?min. Solid state studies suggested the transformation of the crystalline drug to amorphous drug. The size and zeta potential of globules obtained on dilution S-SNEDDS remained similar to L-SNEEDS. In vivo bioavailability study revealed that S-SNEDDS has 2.97 and 1.54-folds higher bioavailability than pure LPV and LPV/RTV formulation, respectively. The optimized S-SNEDDS was found to be stable and had a shelf life of 2.85 years.

Conclusion: The significant increase in drug dissolution and bioavailability by prepared SNEDDS suggest that the developed S-SNEDDS is a useful solid platform for improving oral bioavailability of poorly soluble LPV.