Improved Drug Dissolution Research Articles

Amino functionalized chiral mesoporous silica nanoparticles for improved loading and release of poorly water-soluble drug

In the present paper, chiral mesoporous silica nano-cocoon (A-CMSN) functionalized with amino group was synthesized, and its loading and release of indomethacin (IMC), a poorly soluble drug, was studied. Due to the use of chiral anionic surfactants as a template, A-CMSN possessed 2D hexagonal nano-cocoon morphology with curled channels on its surface, which was quite different from another 2D hexagonal mesoporous silica nanoparticles (MCM-41) with straightway channels. After being loaded into the two silica carriers by hydrogen bond, crystalline IMC converted to amorphous form, leading to the improved drug dissolution. And IMC loading capacity of A-CMSN was higher than MCM-41 because curled loading process originating from curvature chiral channels can hold more drug molecules. Compared with IMC, IMC loaded A-CMSN presented obviously fast release throughout the in vitro release experiment, while IMC loaded MCM-41 released faster than IMC at the initial 5 h then showed controlled slow release afterwards, which was closely related to the mesoporous silica nanoparticles and different channel mesostructures of these two carriers. A-CMSN possessed nano-cocoon morphology with curled 2D hexagonal channel and its channel length was shorter than MCM-41, therefore IMC molecules can easily get rid of the constraint of A-CMSN then to be surrounded by dissolution medium.

ENHANCING DISSOLUTION RATE OF INDOMETHACIN BY IN SITU CRYSTALIZATION; DEVELOPMENT OF ORALLY DISINTEGRATING TABLETS

Objective: The main objective of this study was to investigate the potential of in situ crystallization of indomethacin, in presence or absence of hydrophilic materials, to improve drug dissolution with the goal of developing fast disintegrating tablets.Methods: Indomethacin crystals were prepared by bottom up approach. Water containing hydrophilic additive (polymer or/and surfactant) was added to ethanolic solution of indomethacin while stirring. The selected polymers were hydroxylpropylmethyl cellulose E5 (HPMC E5), polyethylene glycol 6000 (PEG6000) and polyvinylpyrrolidone K40 (PVP K40). The surfactants used were Tween80 and Glucire 44/14. The precipitated particles were collected and air dried. Solid state characterization were performed in addition to in vitro release studies in both acidic (0.1 N HCL) and alkaline medium (phosphate buffer pH 6.8). Optimized formulation was selected to develop fast disintegrating tablets.Results: Thermal behavior suggested modulation in crystalline nature with reduction in particle size that was confirmed by X-ray diffraction results. Infrared spectroscopy excluded any interaction between drug and hydrophilic excipients. Drug dissolution in acid media showed slight improve in drug release, while marked increase was observed in the alkaline media. Combination between Tween80 and HPMC (F7) showed the best dissolution parameters with 5-folds enhancement in release efficiency (RE) compared to pure drug. Formula F7 was successively used to formulate fast disintegrating tablets with prompted release of 58% of the loaded dose and RE of 83%.Conclusion: In situ crystallization of indomethacin is a good approach for enhanced dissolution rate with the presence of hydrophilic additives during precipitation process improving the efficiency.

Electrosprayed mesoporous particles for improved aqueous solubility of a poorly water soluble anticancer agent: in vitro and ex vivo evaluation

Encapsulation of poorly water-soluble drugs into mesoporous materials (e.g. silica) has evolved as a favorable strategy to improve drug solubility and bioavailability. Several techniques (e.g. spray drying, solvent evaporation, microwave irradiation) have been utilized for the encapsulation of active pharmaceutical ingredients (APIs) into inorganic porous matrices. In the present work, a novel chalcone (KAZ3) with anticancer properties was successfully synthesized by Claisen-Schmidt condensation. KAZ3 was loaded into mesoporous (SBA-15 and MCM-41) and non-porous (fumed silica, FS) materials via two techniques; electrohydrodynamic atomization (EHDA) and solvent impregnation. The effect of both loading methods on the physicochemical properties of the particles (e.g. size, charge, entrapment efficiency, crystallinity, dissolution and permeability) was investigated. Results indicated that EHDA technique can load the active in a complete amorphous form within the pores of the silica particles. In contrast, reduced crystallinity (~79%) was obtained for the solvent impregnated formulations. EHDA engineered formulations significantly improved drug dissolution up to 30-fold, compared to the crystalline drug. Ex vivo studies showed EHDA formulations to exhibit higher permeability across rat intestine than their solvent impregnated counterparts. Cytocompatibility studies on Caco-2 cells demonstrated moderate toxicity at high concentrations of the anticancer agent. The findings of the present study clearly show the immense potential of EHDA as a loading technique for mesoporous materials to produce poorly water-soluble API carriers of high payload at ambient conditions. Furthermore, the scale up potential in EHDA technologies indicate a viable route to enhance drug encapsulation and dissolution rate of loaded porous inorganic materials.

Contact Angle Measurements: an Alternative Approach Towards Understanding the Mechanism of Increased Drug Dissolution from Ethylcellulose Tablets Containing Surfactant and Exploring the Relationship Between Their Contact Angles and Dissolution Behaviors.

The addition of surfactant in tablet was a well-defined approach to improve drug dissolution rate. While the selected surfactant played a vital role in improving the wettability of tablet by medium, it was equally important to improve the dissolution rate by permeation effect due to production of pores or the reduced inter-particle adhesion. Furthermore, understanding the mechanism of dissolution rate increased was significant. In this work, contact angle measurement was taken up as an alternative approach for understanding the dissolution rate enhancement for tablet containing surfactant. Ethylcellulose, as a substrate, was used to prepare tablet. Four surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), dodecyltrimethylammonium bromide (DTAB), and sodium lauryl sulfonate (SLS), were used. Berberine hydrochloride, metformin hydrochloride, and rutin were selected as model drugs. The contact angle of tablet in the absence and presence of surfactant was measured to explore the mechanism. The dissolution test was investigated to verify the mechanism and to establish a correlation with the contact angle. The result showed that the mechanism was the penetration effect rather than the wetting effect. The dissolution increased with a reduction in the contact angle. DTAB was found to obtain the highest level of dissolution enhancement and the lowest contact angle, while SDS, SDBS, and SLS were found to be the less effective in both dissolution enhancement and contact angle decrease. Therefore, contact angle was a good indicator for dissolution behavior besides exploring the mechanism of increased dissolution, which shows great potential in formula screening.

Superiority of amino-modified chiral mesoporous silica nanoparticles in delivering indometacin

The present study established indometacin (IMC) delivery system with chiral mesoporous silica nanoparticles (CMSNs) and amino-modified chiral mesoporous silica nanoparticles (Amino-CMSNs) that previously reported as pharmaceutical excipients, and their systemic biological effects, mainly consisting of in vitro drug intestinal permeability, haemolysis assay, in vivo pharmacokinetics, anti-inflammation pharmacodynamics and gastric irritation, were addressed. It turned out that the two IMC delivery systems established by CMSN and Amino-CMSN significantly improved drug intestinal permeability due to the improved drug dissolution caused by conversion of drug crystalline state to amorphous phase. Further, IMC-loaded Amino-CMSN was the superior choice because of its higher dissolution rate. Furthermore, CMSN and Amino-CMSN were safe to be circulated in blood, and Amino-CMSN with significant lower haemolysis ratio than CMSN was better for the minimum haemolytic behaviour. Oral bioavailability and anti-inflammation effect of IMC delivery systems established by CMSN and Amino-CMSN were enhanced compared with IMC, which was attributed to the primary cause of the improvement of IMC dissolution, and Amino-CMSN exhibited better biological effect. As a result of these facts, it is believed that the effective delivery of IMC by Amino-CMSN will provide a new candidate to formulate poorly soluble drugs so as to significantly develop pharmaceutical application.

Optimization of Monolayer Hydrophilic Matrix Tablets Containing Nisoldipine Solid Dispersion Using D-optimal Design

Abstract: Background: Nisoldipine (NIS) is a BCS-class II drug with a low oral bioavailability (~5%). The popular marketed product is a trilayer Geomatrix® system. Although it provides for drug release control of NIS, a trilayer matrix system is a complex design, which is difficult to manufacture on an industrial scale using conventional press. The present study discusses an alternate approach to improve drug dissolution using solid dispersion (SD) method followed by design of a simple monolayer controlled release (CR) matrix system. Methods: Aqueous drug solubility study was carried out at various copovidone levels. NIS-copovidone SD was prepared by hot-melt extrusion and was characterized by infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). A risk assessment based approach was used to select the factors and levels affecting the design of a monolayer matrix tablet. A custom screening design of experiments was used to screen the type and level of excipients followed by a D-optimal mixture design and the dissolution profile was selected as the main response to statistically analyze the data to optimize the final formula. Results: A solvent free approach by hot-melt extrusion was used to prepare NIS-copovidone solid dispersion at 20% drug load, which lead to a significant improvement in dissolution (T90 = 30 min). An interaction between the drug and polymer was revealed in FTIR studies. No drug crystals were seen in SEM studies indicating its presence in a substantially amorphous state in the SD. The statistical analysis of in vitro dissolution data of screening study revealed that high viscosity hypromellose and diluent type had significant effect (p<0.05) on dissolution while the hardness of the tablet had no significant effect (p>0.05). The mixture design thereafter predicted the optimum formula through a significant model. High and low viscosity hypromellose (66:44) at ~17% w/w of matrix provided the desired drug release control. Conclusion: Dissolution enhancement could be attained by SD prepared using solvent free process. D-optimal mixture design approach, where the unit weight remains constant in spite of controlled variation in level of factors studied, was found to be a promising approach in pharmaceutical formulation optimization. A combined approach of SD and CR was found to be a promising strategy for better control of the drug release in a relatively simple monolayer matrix compared to a complex trilayer design. Key words: Nisoldipine, Solid Dispersion, Design of Experiments, Screening, Mixture Design

Improved oral bioavailability of probucol by dry media-milling

The polymer/probucol co-milled mixtures were prepared to improve drug dissolution rate and oral bioavailability. Probucol, a BCS II drug, was co-milled together with Copovidone (Kollidon VA64, VA64), Soluplus, or MCC using the dry media-milling process with planetary ball-milling equipment. The properties of the milled mixtures including morphology, crystal form, vitro drug dissolution and in vivo oral bioavailability in rats were evaluated. Probucol existed as an amorphous in the matrix of the co-milled mixtures containing VA64, which helped to enhance drug dissolution. The ternary mixture composed of VA64, RH40, and probucol showed increased dissolution rates in both sink and non-sink conditions. It also had a higher oral bioavailability compared to the reference formulation. Dry-media milling of binary or ternary mixtures composed of drug, polymer and surfactant possibly have wide applications to improve dissolution rate and oral bioavailability of water-insoluble drugs.

Improved Solubility and Dissolution Rate of Ketoprofen by Beta Cyclodextrin Ternary Complexes Incorporating Hydrophilic Polymers

The aim of the presentstudy wasto improve the aqueous solubility and dissolution rate of a BCS Class-IIdrug,ketoprofen by β-cyclodextrin ternary complexes incorporating hydrophilic polymers polyethylene glycol 6000 (PEG6000) and polyvinyl pyrrolidone (PVP). Initially,ketoprofen (KPF)binary complexes with β-Cyclodextrin (βCD)wereformulated by physical mixing,co-grinding, and solvent evaporation methods which was followed by ternary complex formulation of selected KPF-βCD binary complex incorporatingPEG6000 and PVP.The solvent evaporation method was used in the formulation of ternary complexesof ketoprofen, sincein the beginning of this study, it was proved to be the best methodcomparatively in yielding promising binary complexes of ketoprofen.Ketoprofen formed 1:1 M stoichiometric binary and ternary inclusion complexes as demonstrated by the AL-type of phase solubility graph. An increase in the stability constant value (Kc) of KPF- βCD complex in the presence of PEG6000 and PVP conceded higher complexation competency. FTIR and SEM studies evidenced the perfect ternary inclusion complex formation. Ternary complexes showed improved drug dissolution compared with Ketoprofenalone and KPF-βCD binary complex. The ternary complex containg 1:1:2 molar ratio of KPF:βCD:PEG6000exhibited 94.24% drug dissolution in 2 hours, which was significantly high in relation to ternary complexes containg PVPand it was found to follow first order release mechanism. Complex studied for stabilityshowed no significant change in physical appearance, drug content and drug dissolution characteristic indicating high stability.

Nanoemulsifying drug delivery system to improve the bioavailability of piroxicam

Objective: The aim of this study is to develop and characterize self-nanoemulsifying drug delivery system (SNEDDS) of piroxicam in liquid and solid forms to improve its dissolution, absorption and therapeutic efficacy.Materials and methods: The generation of liquid SNEDDS (L-SNEDDS) was composed of soybean or coconut oil/Tween 80/Transcutol HP (12/80/8%w/w) and it was selected as the optimized formulation based on the solubility study and pseudo-ternary phase diagram. Optimized L-SNEDDS and liquid supersaturatable SNEDDS (L-sSNEDDS) preparations were then adsorbed onto adsorbents and formulated as directly compressed tablets.Results and discussion: The improved drug dissolution rate in the solid supersaturatable preparation (S-sSNEDDS) may be due to the formation of a nanoemulsion and the presence of drug in an amorphous state with hydrogen bond interaction between the drug and SNEDDS components. In vivo pharmacokinetic studies on eight healthy human volunteers showed a significant improvement in the oral bioavailability of piroxicam from S-sSNEDDS (F12) compared with both the pure drug (PP) and its commercial product (Feldene®) (commercial dosage form (CD)). The relative bioavailability of S-sSNEDDS (F12) relative to PP or CD was about 151.01 and 98.96%, respectively.Conclusion: The obtained results ratify that S-sSNEDDS is a promising drug delivery system to enhance the oral bioavailability of piroxicam.

Thiolated Cyclodextrin: Development of a Mucoadhesive Vaginal Delivery System for Acyclovir

The objective of this study was the development of a mucoadhesive vaginal delivery system for acyclovir (Acv). Sodium-per-iodate (NaIO4) was used to introduce aldehyde substructures into beta-cyclodextrin (β-CD) by oxidative cleavage of vicinal diol bonds. Cysteamine was covalently attached to β-CD-CHO via reductive amination. Ellman’s reagent was utilized for quantification of free thiol groups attached and resazurin assay was used for cytotoxicity studies. Mucoadhesive properties were evaluated on porcine vaginal mucosa in comparison to intestinal mucosa. Quantification of thiol groups revealed 851.84 ± 107, 1040.44 ± 132, and 1563.72 ± 171 μmol/g of free thiol groups attached to the β-CD-SH851, β-CD-SH1040, and β-CD-SH1563, respectively. β-CD-SH derivatives at concentrations of 0.5% (m/v) did not show significant reduction of viability of Caco-2 cells within 24 h. Furthermore, water solubility of β-CD-SH1563 was improved 7.6-fold in comparison to unmodified β-CD. β-CD-SH851, β-CD-SH1040, and β-CD-SH1563 showed 5.84-, 15.95-, and 17.14-fold improved mucoadhesive properties on porcine vaginal mucosa and 3-, 12.47-, and 32.13-fold on porcine intestinal mucosa, respectively. Inclusion complex of Acv with β-CD-SH1563 resulted in significantly improved drug dissolution. According to the results, β-CD-SH derivatives might be promising new tools for local vaginal delivery of Acv.

The Evaluation of In Vitro Drug Dissolution of Commercially Available Oral Dosage Forms for Itraconazole in Gastrointestinal Simulator With Biorelevant Media

The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, gastrointestinal simulator (GIS), in assessing the drug dissolution of 2 commercially available oral dosage forms for itraconazole (ICZ). The GIS consists of 3 chambers, mimicking the upper gastrointestinal tract. In vitro dissolution of ICZ capsule or oral solution was evaluated in United States Pharmacopeia apparatus II and GIS. To investigate the suitability of fasted state simulated intestinal fluid (FaSSIF) to predict better in vivo, FaSSIF as well as phosphate buffer were used as dissolution media. Area under the dissolved drug amount-time curve (AUDC) was calculated for each dosage form in each apparatus, and the ratios of AUDCoral solution to AUDCcapsule were compared with human pharmacokinetic data. Based on this comparison, GIS with FaSSIF can adequately distinguish the pharmacokinetic profiles of 2 oral dosage forms for ICZ. Additionally, Caco-2 cell transepithelial transport study in combination with GIS revealed that improved drug dissolution by formulations resulted in enhanced permeation of ICZ through cell monolayer, suggesting the observed ICZ concentration in the GIS will directly reflect systemic exposure. These results indicate GIS would be a powerful tool to assess the formulations of ICZ as well as other Biopharmaceutics Classification System class II drug formulations.

AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

Hot-melt extrusion and prilling as contemporary and promising techniques in the solvent free production of solid oral dosage forms, based on solid dispersions

Hot melt extrusion and prilling are gaining importance as solvent free and continuous techniques in the production of solid oral dosage forms with added value, by incorporating active compound in a molten carrier which is further solidified to form solid dispersion. This article reviews these two techniques in terms of understanding process basics, equipment characteristics, required properties of processed materials and application of the processes for development of solid oral dosage forms. Studies revealed that both hot-melt extrusion and prilling are regarded as simple, robust and continuous methods for processing different types of materials and production of solid dosage forms based on solid matrices. However, understanding of their concepts and requirements together with careful material selection is crucial for stable material processing and obtaining stable products of high-quality. Hot-melt extrusion proved to be a suitable method for production of modified release dosage forms, taste masked dosage forms and dosage forms offering improved drug dissolution rate and solubility. Prilling till now has been successfully applied just in the production of multiple unit drug delivery systems for immediate and sustained drug delivery. Further studies on product development and process understanding are required for full implementation of prilling in the pharmaceutical field.

Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers

ABSTRACTObjectives: The purpose of this study was to develop mesoporous silica materials incorporated with poorly water-soluble drug atorvastatin calcium (AC) in order to improve drug dissolution, and intended to be orally administrated. A comparison between 2D-hexagonal silica nanostructured SBA-15 and mesocellular siliceous foam (MSF) with continuous 3D pore system on drug release rate was investigated.Methods: AC-loaded mesoporous silicas were characterized thorough N2 adsorption-desorption analysis, Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and dynamic light scattering (DLS).Results: Results demonstrated a successful incorporation of AC into the silica-based hosts. The results taken from the drug release tests were also analyzed using different parameters, namely similarity factor (f2), difference factor (f1), dissolution efficiency (DE%), mean dissolution rate (MDR) and dissolution time (tm%). It confirmed a significant enhancement in the release profile of atorvastatin calcium with SBA-15, and MSF as drug carrier. Moreover, in comparison with SBA-15, MSF showed faster release rate of AC in enzyme-free simulated gastric fluid (pH 1.2).Conclusion: We believed that our findings can help the use of mesoporous silica materials in improving bioavailability of poorly water-soluble drugs.

Enhancement of Carvedilol Dissolution; Surface Solid Dispersion Versus Solid Dispersion

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

Optimization of Cefixime Nanosuspension to Improve Drug Dissolution

Background: The aim of this study was to prepare and characterize cefixime nanosuspensions in order to enhance the dissolution rate and solubility of this drug. Methods: Nanosuspensions were prepared using sonoprecipitation method and the effects of surfactant type, surfactant and solid content, sonication power input and interval of acid addition on the yield and particle size of nanosuspensions were investigated. Results: Particle size and yield of the optimal nanosuspension formulation were 266±10 nm and 35±2%, respectively. Scanning electron microscopy (SEM) results showed a nearly spherical morphology for cefixime nanoparticles. Thermal analysis indicated that there was a partial crystalline structure in the nanoparticles and in vitro dissolution rate of the drug was significantly increased by the reduction in particles size. Conclusions: Sonoprecipitation was shown to be a successful method to produce cefixime nanosuspensions and the optimum conditions of the process were introduced.

IMPROVEMENT OF DISSOLUTION RATE OF FEBUXOSTAT USING HYBRID TECHNIQUE OF SPHERICAL CRYSTALLIZATION AND SOLID DISPERSION

The present study was carried out with an aim to improve dissolution rate of febuxostat (FBX, BCSclass II) drug. Spherical agglomerates were prepared by hybrid technique of spherical crystallization and solid dispersion using different ratios of FBX and polymer (PVP K30, HPMC E3LV and chitosan). Drug excipient compatibility study was evaluated by Fourier transform infrared spectroscopy and X-ray diffractometry. Scanning electron microscopy was used for measurement of size of agglomerate. In vitro dissolution study of prepared spherical agglomerates was compared with untreated FBX and marketed formulation in phosphate buffer pH 6.8. The ratio of drug to polymer also affected the drug dissolution results. Drug excipient compatibility study showed no interaction between FBX and PVP K30 (1:5) polymer. The use of PVP K30 (1:5) resulted in partial amorphization and improved drug dissolution. Direct compression method can be adopted in manufacturing to simplify the validation efforts. The performance of the formulated product was superior to the marketed product in the in vitro dissolution test.

Cocrystal habit engineering to improve drug dissolution and alter derived powder properties.

Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.

Improvement in oral bioavailability and dissolution of tanshinone IIA by preparation of solid dispersions with porous silica.

This study aims to evaluate the oral bioavailability and dissolution of tanshinone IIA (tanIIA) by preparation of solid dispersions (SDs) with porous silica. SDs of tanIIA were prepared using a solvent method. The physicochemical properties, dissolution property, drug stability and in-vivo performance of the SDs prepared were all evaluated. Compared with tanIIA alone and corresponding physical mixtures, tanIIA from SDs showed remarkably improved in-vitro dissolution rate. After forming the SDs, tanIIA changed into an amorphous state, which can infer from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Fourier transform infrared spectroscopy (FTIR) also revealed the presence of interactions between tanIIA and porous silica in SDs. During the stability study, there is no significant decreasing in either the in-vitro dissolution or the drug content, which was observed following storage at room temperature for 12 months. The results of a pharmacokinetic study in rats showed the areas under the concentration-time curve from 0 h to 24 h (AUC0-24h ) for the SDs and tanIIA were 1019.87 ± 161.819 mg/h per litre and 343.70 ± 75.628 mg/h per litre, respectively. SDs with porous silica as carrier could achieve superior oral bioavailability by improving drug dissolution, whereas drug stability could be maintained.

Liquid anti-solvent recrystallization to enhance dissolution of CRS 74, a new antiretroviral drug

This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion.