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.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

Preparation and in vitro characterization of a semi-solid dispersion of flurbiprofen with Gelucire 44/14 and Labrasol

Flurbiprofen is characterized by low solubility in water and has been implicated in causing gastro intestinal ulceration. The purpose of this study was to increase the dissolution characteristics of flurbiprofen by preparing a semi-solid dispersion with Gelucire 44/14 and Labrasol (F1) in hard gelatin capsules. The results were evaluated by comparing several in vitro parameters with powdered drug filled into hard gelatin capsules. The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; citrate buffer pH 4.5; phosphate buffers pH 6.8 and 7.2, and water). Characterization of semi-solid dispersions and physical mixtures was performed using Fourier transform-infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), particle size analysis and turbidity measurement. The results suggest that all semi-solid dispersions of flurbiprofen showed a remarkable improvement in the rate and extent of drug dissolution. The dissolution of F1 exhibited significant improvement in all dissolution media at different pH. The dissolution of flurbiprofen within 30 min in pH 1.2 was (55%), in pH 4.5 67%, pH 6.8 96%, pH 7.2 98% and in water 88%. FT-IR indicated no strong drug: excipient interactions, and DSC studies indicated a loss of crystalline nature of the drug. The particle size analysis revealed an average size diameter from 194 to 278 nm. Therefore, a semi-solid dispersion of flurbiprofen with Gelucire and Labrasol may have the potential of improved bioavailability because of the enhanced in vitro properties.     

Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol

Piroxicam is a nonsteroidal anti-inflammatory drug that is characterized by low solubility-high permeability. The present study was designed to improve the dissolution rate of piroxicam at the physiological pH's through its increased solubility by preparing semi-solid dispersions of drug using Gelucires and Labrasol. These excipients are essentially characterized by their melting points and HLB (hydrophilic-lipophilic balance) values. The dissolution tests of the preparations were performed in the media with different pH's. Differential scanning calorimetry (DSC), were used to examine the interaction between piroxicam and excipients. Gelucire 44/14 and Labrasol at the concentration of 15% w/v in water provided 20- and 50-fold increase in the solubility of piroxicam, respectively. The semi-solid dispersion containing 1/20 of drug/excipient mixture (20% Gelucire 44/14 and 80% Labrasol in w/w) produced the dissolution not less than 85% of piroxicam within 30 min in each dissolution media (simulated gastric fluid (SGF), pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). DSC analysis of this semi-solid dispersion indicated that there was no chemical reaction between the drug and excipients, and that a solid-state solution of piroxicam with excipient formed.     

Influence of Copolymer Composition on <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly water-soluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50–60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC_0-4h and in vivo AUC_0-24h for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.     

Hydration of an amphiphilic excipient, Gelucire 44/14

The incorporation of drugs into Gelucires has been reported to increase the dissolution rate of poorly soluble drugs, often leading to improved drug bioavailability. In pharmaceutical applications, it is important to know how the excipient interacts with the drug, and how the mixture behaves during manufacturing, storage as well as during administration. The uptake of water by an amphiphilic excipient, Gelucire 44/14, has been investigated in two ways: storage in humid air and addition of liquid water. During exposure to humid air, the uptake goes in stages that correspond to the dissolution of the components of the excipient, starting with the most hydrophilic ones: glycerol, then polyethylene glycol (PEG), PEG esters (PEG monolaurate and PEG dilaurate), and finally glycerides (trilaurin). At each stage, the remaining crystals are in equilibrium with an interstitial solution made of water and the dissolved components. In this range of hydrations, the total uptake is close to the sum of the equilibrium hydrations of the components. In the pharmaceutical formulation, the active ingredient could dissolve in the liquid phase. At larger hydrations, obtained through addition of liquid water, the state of Gelucire 44/14 differs from those of its components. Gelucire 44/14 forms a lamellar phase and this phase melts at 30 degrees C whereas the pure PEG esters form hexagonal and cubic mesophases. The cubic mesophases do not melt until the temperature exceeds 40 degrees C. At body temperature, all crystals in Gelucire 44/14 melt to an isotropic fluid as soon as the total water content exceeds 5%. Therefore the formulation of amphiphilic excipients can be optimized to avoid the formation of mesophases that impede dissolution of the excipient at body temperature.     

Physicochemical investigation of the solid dispersion systems of etoricoxib with poloxamer 188

Solid dispersion systems of a poorly water-soluble drug, etoricoxib were prepared with poloxamer 188 in 1:0.5, 1:1.5 and 1:2.5 ratios and evaluated by FTIR, powder XRD and dissolution studies. Physical studies demonstrated a strong hydrogen bonding with significant decrease in the crystallinity and formation of amorphous etoricoxib in its binary systems. All binary systems of etoricoxib showed faster dissolution than pure drug alone (P?<?0.001). However, 1:2.5 proportion of etoricoxib: poloxamer 188 showed superior performance (DE₄₅: 71.27%?±?3.85) in enhancing solubility and dissolution rate of etoricoxib suggesting optimum ratio of the carrier.     

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.     

Melt extrusion--an alternative method for enhancing the dissolution rate of 17beta-estradiol hemihydrate.

17Beta-estradiol hemihydrate (17beta-E2) is a poorly water-soluble drug. Physical methods for improving the solubility and dissolution rate, e.g. micronization, have certain inherent disadvantages. The method of choice in this study, melt extrusion, proved to overcome many of the shortcomings of conventional methods. Different compositions of excipients such as PEG 6000, PVP (Kollidon 30) or a vinylpyrrolidone-vinylacetate-copolymer (Kollidon VA64) were used as polymers and Sucroester WE15 or Gelucire 44/14 as additives during melt extrusion. The solid dispersions resulted in a significant increase in dissolution rate when compared to the pure drug or to the physical mixtures. For example, a 30-fold increase in dissolution rate was obtained for a formulation containing 10% 17beta-E2, 50% PVP and 40% Gelucire 44/14. The solid dispersions were then processed into tablets. The improvement in the dissolution behavior was also maintained with the tablets. The USP XXIII requirement for estradiol tablets reaching greater than 75% drug dissolved after 60 min was obtained in this investigation.     

Physicochemical characterization and dissolution properties of meloxicam-gelucire 50/13 binary systems

A solid dispersion of Meloxicam (MX), a poorly soluble, non steroidal anti-inflammatory drug, and Gelucire 50/13 was prepared by spray drying. Spherical microparticles were yielded with smooth surfaces as observed by scanning electron microscopy. According to differential scanning calorimetry and powder X-ray diffractometry analysis, MX was transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the crystalline peaks. The dissolution tests at pH 7.4 revealed that the dissolution rate of encapsulated MX was 2.5-fold higher than that of the corresponding physical mixture and fourfold higher than the drug alone, respectively. The microparticles prepared at a ratio of 1:4 (drug/Gelucire) exhibited a 4-fold higher anti-inflammatory activity on the paw edema of rats in comparison to the drug alone. All in all, this work reveals that spray drying is a suitable technique for preparation of solid dispersions with improved biopharmaceutical and pharmacological characteristics of MX.     

The Physicochemical and Pharmacokinetic Bases for the Biopharmaceutical Evaluation of Drug Biological Availability in Pharmaceutical Formulations

Abstract: The operational determination of the bioavailability of a vital drug from its pharmaceutical formulation by the extent and rate of its appearance in the blood and tissues of an intact biological organism is termed biopharmaceutics. Such bioavailability is a complex function of the physicochemical factors that determine its stability in the formulation and in the biological fluids; the rate of release of drug particles from, or disintegration of, the formulation matrix; the rate of dissolution of the dispersed drug particles as affected by the pH, volume, and agitation of the dissolution media; the solubility of the drug in the solvent; its transport to the absorption site; the pKa of the dissolved substance that determines the concentration of neutral species at the pH at the site; the partition of dissolved drug into the lipid-like membranes and the subsequent rate of diffusion into the body compartments. Pharmacokinetics determines the amounts of drug absorbed, the rate of absorption and release from the pharmaceutical formulation in the intact biological system. Experimental data may be obtained from amounts of drug and/or metabolites monitored in the urine, faeces and blood as functions of time. Total amounts excreted and areas under blood level-time curves with their defined limitations are one set of criteria of bioavailability. Rates of absorption, deduced from rates of change of blood level and excretion, form another set of criteria whose various limitations are also defined. Dissolution rate studies have limited a priori value in predicting bioavailability but may be useful in quality control procedures when correlated with biopharmaceutical data. Although many mathematical functions may be operationally useful in characterizing in vitro dissolution rates of drugs from dosage forms, the most valid presentation of data is the percentage og drug released at various time intervals.     

Properties of solid dispersions of piroxicam in polyvinylpyrrolidone.

Solid dispersions of piroxicam were prepared with polyvinylpyrrolidone (PVP) K-17 PF and PVP K-90 by solvent method. The physical state and drug:PVP interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR analysis demonstrated the presence of intermolecular hydrogen bonding between piroxicam and PVP in solid dispersions. These interactions reflected the changes in crystalline structures of piroxicam. The amorphousness within the PVP moeity might be predicted in piroxicam dispersions by the disappearance of N-H or O-H peak of piroxicam. Dissolution studies indicated a significant increase in dissolution of piroxicam when dispersed in PVP. The better results were obtained with the lower molecular weight PVP K-17 than with higher molecular weight PVP K-90. The non-amorphous solid dispersions in PVP K-17 showed almost equally fast dissolution rates to amorphous dispersions in PVP K-90. The mechanism of dissolution of solid dispersion in PVP K-90 is predominantly diffusion-controlled due to the very high viscosity of PVP K-90. Dissolution was maximum with the amorphous solid dispersions containing drug:PVP K-17 1:5 and 1:6 which showed a 40-fold increase in dissolution in 5 min as compared with pure drug. Copyright     

Selecting oral bioavailability enhancing formulations during drug discovery and development

Introduction: The role of chemical structure, lipophilicity, physico-chemical, absorption, distribution, metabolism, excretion, toxicity (ADMET) and biopharmaceutical properties of compounds including bioavailability are critical in drug discovery and drug dosage forms design.

Areas covered: The authors discuss a number of parameters including computational approaches used for selected chemical structures with biological activity for lead optimization and chemogenomics and preclinical studies for ADMET process development of ligand properties. The authors also look at a number of other parameters including: early drug product formulations with method selection based on the biopharmaceutical classification system (BCS); in vitro–in vivo correlation (IVIVC) and different formulation strategies to enhance solubility; dissolution rate and permeability; bioavailability evaluation and quality by design as an opportunity to develop ‘safe space' regions, where bioavailability is unaffected by pharmaceutical variations.

Expert opinion: The biopharmaceutical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The genomic methodology, coupled with combinatorial chemistry, high-throughput screening, structure-based design and in silico ADMET would yield parameters as a starting point for the biopharmaceutical properties determination in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable, but pharmacokinetics is the critical step. Selection of drug formulations based on the BCS, IVIVC are the principal aspects to enhance the solubility and dissolution rate, while a rationale management of pharmaceutical and technological factors will enhance the bioavailability.     

Effect of a basic organic excipient on the dissolution of diclofenac salts

Dissolution of diclofenac from compressed discs containing mixtures of a diclofenac salt and a basic excipient, in various w/w ratios, was examined. Two diclofenac salts, diclofenac deanol (DDNL) and diclofenac tert-butylamine, and the basic excipient 2-amino-2-methyl-1,3-propanediol (AMPD) were examined. Inclusion of the soluble basic excipient at high loadings enhanced the dissolution rate of diclofenac tert-butylamine fivefold; however, it retarded dissolution of the DDNL salt 40-fold in the weight fraction range 40-80% AMPD, despite the fact that AMPD is more than four times more soluble than DDNL. These findings were attributed to the solubilities of salts formed between diclofenac and the basic excipient used. The "salt conversion model" was developed to predict dissolution from mixtures of a salt of an ionizable drug and an ionizable excipient capable of forming a salt with the drug. Deviations from the model at high weight fractions of base and, in the case of the systems containing the more soluble drug, at low weight fractions of base were attributed to carrier-controlled dissolution. The present work illustrates that the solubility of potential salts, which may form between the drug and ionizable excipients present has an important influence on the dissolution of the drug from such compressed mixtures.     

Interaction Studies Between Levodopa and Different Excipients to Develop Coground Binary Mixtures for Intranasal Application

Levodopa (LEVO) as the gold standard in the treatment of Parkinson’s disease is usually administrated per os but its bioavailability is low. The intranasal administration is a potential alternative route to increase bioavailability of the drug and treat the off period. Our aim was to develop LEVO-containing binary nasal powders with different excipients by dry cogrinding process. The interactions between the components were examined. The optimized cogrinding process parameters (LEVO:excipient ratio and grinding time) resulted in the desired particle size range (5-40 μm). The α-cyclodextrin and poly(vinylpyrrolidone) (PVP) had an intensive crystallinity degree reducing effect on LEVO measured by XRPD, and they functioned as cogrinding agents. Hydroxypropyl methylcellulose, poly (vinyl alcohol) (PVA), and D-mannitol associate around the LEVO crystals preventing its crystalline structure. Hydrogen bonding was detected only for LEVO-PVP and LEVO-D-mannitol used Fourier-transformed infrared spectroscopy. Chemical degradation of LEVO in the products was not detected even after the accelerated stability test. The dissolution profile of the products can be characterized by the first-order kinetic model with different dissolution rate. The dissolution rate of LEVO was increased with α-cyclodextrin and PVP, and the drug release decreased in the case of hydroxypropyl methylcellulose, PVA, and D-mannitol compared to the LEVO powder.     

Characterization and Physical Stability of Tolfenamic Acid-PVP K30 Solid Dispersions

Obtaining a stable formulation with high bioavailability of a poorly water-soluble drug often presents a challenge to the formulation scientist. Transformation of the drug into its more soluble high-energy amorphous form is one method used for improving the dissolution rate of such compounds. The present study uses the spray-drying technique for preparation of solid dispersions (SDs) of tolfenamic acid (TA) and polyvinylpyrrolidone K-30 (PVP). The SDs and TA in the form of a spray-dried powder were initially characterized and compared with a physical mixture and starting materials. Stability of the SDs was monitored over 12 weeks at 25°C and 60% RH. XRPD studies revealed changes in solid state during the formation of the SDs and indicated the presence of TA in the amorphous state. FTIR, together with TGA, suggested molecular interactions (hydrogen-bonding) in the SDs. Dissolution studies proved an increase in the dissolution rate of TA from all SDs. The SDs with higher content of PVP retained TA in the amorphous state throughout the stability study. However, SDs with lower content showed recrystallization of TA after 1 week. Thus, this study reveals the possibility of preparing stable SDs of amorphous TA in PVP with improved dissolution rate.     

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.     

Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective

The use of lipid-based dosage forms for enhancement of drug absorption or delivery has drawn considerable interest from pharmaceutical scientists. The unique characteristics of these dosage forms, however, present significant challenges to pharmaceutical industry and regulatory agencies in many ways. For example, safety assessment is necessary when the use of a new lipid excipient is considered. An important question for lipid formulation is whether the drug remains in solubilised form along the gastrointestinal (GI) tract after it is administered. Certain lipid excipients and surfactants have been reported to change intestinal permeability or interfere with enzyme/transporter activity, thereby affecting drug bioavailability. The potential influence of biopharmaceutical and/or pathophysiological factors on the drug or lipid excipient(s) needs to be explored. For a complex lipid-based dosage form, the conventional in vitro dissolution methods may not be appropriate for predicting in vivo performance in view of the convoluted GI processing of the lipid vehicle and formulation Of paramount importance is to identify any gaps in the scientific understanding of lipid-based dosage forms so that regulatory issues can be addressed. More mechanistic studies should be encouraged to facilitate a better understanding of the pharmaceutical characteristics of lipid formulations and complex interactions between lipid excipient, drug and physiological environment. This review discusses some regulatory considerations in the use of lipid excipients and delivery systems for pharmaceutical development. Implications in the regulatory determination of pharmaceutical equivalence, bioequivalence and therapeutic equivalence are also illustrated.     

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.     

Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs

Objectives Drug‐excipient binding can affect in‐vitro drug release. Literature suggests that drug‐excipient ionic binding interaction that is not disrupted by physiological salt concentration in the dissolution medium can impact a drug's oral bioavailability. We investigated whether nondisruption of interaction by physiological salt concentration was an adequate predictor of its biorelevance using the binding of a model amine high dose drug brivanib alaninate (BA) to croscarmellose sodium (CCS) as an example. Methods BA was formulated into an immediate release tablet using CCS as disintegrant by a wet granulation process. In‐vitro drug release was carried out as a function of pH and buffer concentration of the medium. BA‐CCS binding was studied in buffer solution and data fitted to a Langmuir isotherm. A simulation model and an isothermal titration calorimetry method were developed to assess the bioavailability risk and strength of drug‐excipient binding interaction, independent of physiological salt concentration consideration. Key findings BA‐CCS binding was pH‐dependent, reversible, ionic, and not disrupted by increasing the buffer concentration in the dissolution medium. Absorption simulation predictions of no effect of CCS binding on BA's bioavailability were confirmed by a monkey pharmacokinetic study. Conclusions A pH‐dependent and reversible weak drug‐excipient binding interaction is unlikely to affect the oral bioavailability of high dose drugs.