pH-independent Release Research Articles

An approach for pH-independent release of poorly soluble ionizable drugs using hot-melt extrusion

Hot melt extrudates with combinations of Soluplus® and Aqoat® AS-LF or Eudragit® E PO were investigated to improve drug release and to overcome the pH-dependent release of poorly water-soluble basic (itraconazole, ITZ) and acidic (mefenamic acid, MFA) drugs. The release of ITZ was improved in both 0.1 N HCl and PBS pH 6.8 by hot-melt extrusion with combinations of Soluplus®:Aqoat® AS-LF and can be adjusted by varying the ratio of the polymers. At the ratio Soluplus®:Aqoat® AS®LF 75:25, an almost pH-independent release was achieved without any drop in the drug concentration within 24 h. A pH-independent and extended release (over 24 h) was obtained from milled extrudates when formulated in erodible matrix tablets using 15 % Methocel® K15M as the carrier. The release of MFA from extrudates with Soluplus® was immediate only in PBS pH 6.8. From extrudates with cationic Eudragit® E PO the release of MFA was slow in 0.1 N HCl and PBS pH 6.8, due to poor drug solubility and insoluble Eudragit® EPO, respectively. However, in the medium with an intermediate pH of 5.5, both MFA and Eudragit® E PO are highly ionized, and the release was fast, complete, and stable within 24 h. These release behaviors could be to some degree applicable for immediate or enteric, but not for extended-release formulations.

Formulation, Optimization and Evaluation of Solid SMEDDS of Pioglitazone

This investigation assessed 32 formulations of liquid self-microemulsifying drug delivery system (L-SMEDDS) for pioglitazone (PGZ). The optimal PLS12 formulation comprises 40% capmul MC8 (oil), 40% cremophore RH40 (surfactant), and 20% PEG (co-surfactant). PLS12 exhibited approximately 75 nm droplet size, below 200 nm, and a PDI of 0.47, indicating nanosized droplets with uniform distribution. The formulation demonstrated stability, and achieved supreme drug loading capacity. The enhanced L-SMEDDS was solidified into solidified SMEDDS utilizing Sylloid 244 FP, subsequently in a free-flowing powder without drug interactions. Tablets were successfully formulated by incorporating S-SMEDDS with diverse tableting excipients. The selected tablet batch passed quality control and stability tests. The tablet exhibited a rapid and pH-independent release profile. The combined impact of SMEDDS and tablets collectively enhanced the solubility and dissolution of PGZ hydrochloride

Agarose as a tunable platform for oral drug delivery: Controlled release of a highly soluble drug, theophylline, within a sequentially-changing-pH medium

The purpose of this study was to expand the use of freeze-dried agarose-based systems for the oral controlled release of highly water-soluble drugs. Three additives (Eudragit S-100 and RL-PO and Labrafac) were included within these systems together with Theophylline. The release of this drug from the rehydrated systems was evaluated in deionized water and in a sequentially-changing-pH medium that simulated the conditions under oral administration. Considering the results obtained in the preliminary release test in water, only the Eudragit-containing compositions were further characterized. The theophylline release in a sequentially-changing-pH medium showed two different patterns that mainly depend on the additive nature: those systems containing Eudragit S-100 showed a similar behaviour to that observed in the absence of additives while the presence of Eudragit RL-PO yields a progressive and pH-independent release. Agarose-based systems were capable of accommodating additives that allows tailoring a controlled release of theophylline, a highly soluble drug.

Polyelectrolyte-based solid dispersions for enhanced dissolution and pH-Independent controlled release of sildenafil citrate

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.

Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended-Release Nifedipine in Healthy Subjects.

Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effects of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short-term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of area under the concentration-time curve from time zero to the last measurable timepoint (AUC0-t ) and maximum plasma concentration (Cmax ) of nifedipine to 132.6% (90% confidence interval (CI): 120.6-145.7%) and 112.8% (90% CI: 100.8-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI: 109.7-132.5%) and 122.5% (90% CI: 113.7-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC0-t and Cmax was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112% and 133% with and without short-term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposure changes for both formulations, which would warrant additional assessment.

Bioequivalence and Relative Bioavailability Studies to Assess a New Acalabrutinib Formulation That Enables Coadministration With Proton-Pump Inhibitors.

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration with proton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N=30, N=66, N=20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean [% coefficient of variation, CV]) were comparable for AT versus AC (AUCinf 567.8ngh/mL [36.9] vs 572.2ngh/mL [38.2], Cmax 537.2ng/mL [42.6] vs 535.7ng/mL [58.4], respectively); similar results were observed for acalabrutinib's active metabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean Cmax for acalabrutinib was lower when AT was administered in the fed versus the fasted state (Cmax 255.6ng/mL [%CV, 46.5] vs 504.9ng/mL [49.9]); AUCs were similar. For AT+PPI, geometric mean Cmax was lower (371.9ng/mL [%CV, 81.4] vs 504.9ng/mL [49.9]) and AUCinf was higher (AUCinf 694.1ngh/mL [39.7] vs 559.5ngh/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.

In Vitro and In Vivo Evaluations of Berberine-Loaded Microparticles Filled In-House 3D Printed Hollow Capsular Device for Improved Oral Bioavailability.

The low oral bioavailability, short biological half-life, high dose, and frequent dosing of berberine (BBR) contribute to its restricted clinical use despite its extensive pharmacological activity. Thus, the objective of this study was to formulate sustained-release microparticles (MPs) using a pH-independent release polymer and to evaluate their potential to improve the oral bioavailability of BBR. BBR loaded MPs were prepared using the emulsion crosslinking method and evaluated for particle size, circularity, morphology, entrapment efficiency, solid-state analysis, swelling index, and in vitro BBR release study fitted with different models of release kinetics. The MPs exhibited desired particle sizes ranges between 11.09–11.62 μm and were almost spherical in shape, as confirmed by the circularity value and micrographic images. A loss of BBR crystallinity was observed after encapsulation in MPs, as evident from various solid-state analyses. The final optimized batch (F3) showed highest % BBR entrapment efficiency value of 81.63% ± 4.9. The in vitro BBR release performance in both acidic and alkaline media showed the desired sustained release behavior from the crosslinked MPs, where the maximum BBR release was observed at alkaline pH, which is in accordance with the swelling study data. In the in vivo study, the oral absorption profiles of BBR from both pristine and MPs formats were investigated using in-house prototyped 3D printed hollow capsules as a unit dose carrier. In vivo data showed sustained and prolonged absorption behavior of BBR from MPs compared to their pristine counterparts, which resulted in a cumulative increment of relative oral bioavailability to mitigate the aforementioned issues related to BBR. Graphical Supplementary InformationThe online version contains supplementary material available at 10.1208/s12249-022-02241-9.

Hydrodynamically Balanced Capsule of Famotidine: An Improved Delivery via Gastroretentive Hydrogels

Objective: The aim of the present study was to increase the absolute bioavailability of famotidine, enhanced patient compliance in the treatment of peptic ulcer by increasing its gastric residence time and controlled local release of drug upto 12 hours. Materials and Methods: Hydrodynamically balanced capsules of famotidine were prepared, consisting of floating matrix granules, which formed hydrogels. Effects of different formulation variables namely hypromellose (HPMC 4000 cps, HPMC 5600 cps, HPMC 15000 cps), effervescent agent (potassium bicarbonate) and mixing time were studied. Optimization study included 23 full factorial design with t50% and t80% as the kinetic parameters (response variable). Matrix characterization included scanning electron microscopy. All prepared formulations were evaluated to various parameters such as micromeritics properties, % buoyancy and in vitro drug release studies. Results and Discussion: The optimized formulation (F4) remains buoyant for more than 12 hrs. The in-vitro drug release study indicated that increasing the viscosity of HPMC resulted in sustained drug release with long floating duration. SEM studies showed definite entrapment of the drug in the matrix and hydrogel formation. Results showed a pH independent but polymer viscosity dependent drug release profile. The release kinetics followed Higuchi model and mechanism of release was found to be non-Fickian diffusion. Conclusion: Famotidine-loaded hydrodynamically balanced capsules were successfully prepared and prove to be useful for prolonged gastric residence of the drug, better bioavailability, patient compliance and improve delivery for enhanced anti-ulcer activity.

Modular solid dosage form design – Application to pH-independent release of a weak-base API

A novel approach to solid dosage form design is investigated, whereby instead of blending the ingredients and subsequently compacting the mixture, the dosage form is made by assembling prefabricated components, each with a specific function. The approach was used to formulate a weak-base API (active pharmaceutical ingredient), such that the modular dosage forms exhibited pH-independent drug release. Tablet-like dosage forms of ciprofloxacin (CPR), used as model weak-base drug, were prepared in order to generate dosage forms exhibiting pH-independent drug release. The dosage forms were made by assembling two types of prefabricated modules onto 3D stacks. The modules were hydroxypropyl methylcellulose circular film wafers, loaded with either CPR or citric acid (CA). CA-wafers served the function of pH-modifier modules in the microenvironment of the dosage form during the dissolution process. In vitro drug release from dosage forms consisting of CA- and CPR-wafers stacked in alternate sequence was compared with the release from assemblies containing CPR-wafers only, under pH = 1.2 and pH = 6.8 conditions. In the absence of CA-wafers, CPR release was ~25-fold slower at pH = 6.8 compared to pH = 1.2. Inclusion of CA-wafers in the dosage form assembly accelerated and decelerated drug release at pH = 6.8 and pH = 1.2, respectively, which resulted in overlapping drug release profiles under the two pH conditions. The two drug release profiles met the criteria for sameness as assessed by the f1 (difference) and f2 (similarity) factors. Modeling of drug release kinetics pointed toward polymer erosion as the primary mechanism of drug release for the overlapping pH = 1.2 and pH = 6.8 profiles. In terms of their drug release properties, the multi-modular dosage form assemblies exhibited the attributes and behavior of single bodies, rather than the combined contributions from multiple individually-operating modules. The initial geometry of the dosage form, characterized by the surface area (SA), volume (V) and SA/V ratio accounted for drug release kinetics in the same fashion as for traditional tablet compacts.

Improvement of Physicochemical and Solubility of Dipyridamole by Cocrystallization Technology

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and cocrystal technology tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving physicochemical properties and dissolution behavior of DP under neutral conditions. Molecular docking method was used to identify the suitable conformer. Upon optimization of the ratio of TA to DP (molar ratio of 1:1, 1:2 and 1:3) was prepared by a solvent assisted griding method. Scanning electron microscopy images revealed that formation of DP-TA co crystals supported by supported by powder X-ray diffraction and differential scanning calorimetry analyses. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP and TA resulting in pH independent dissolution behavior of drug substance. The study confirmed the selection of proper coformer and exhibited enhanced physicochemical, solubility and stability of the Dipyridamole cocrystals. Hence, based upon results it revealed that cocrystallization helps in improving the physicochemical properties of the API.
 Keywords: Dipyridamole, Coformer, Molecular docking, Radar chart, solvent assisted griding, Cocrystals

Microenvironmental pH-modified Amisulpride-Labrasol matrix tablets: development, optimization and in vivo pharmacokinetic study.

Amisulpride (AMS) is atypical antipsychotic with a weak basic nature (pKa 9.37), which results in low solubility in the high pH of the intestine. It is also recognized as a substrate of P-glycoprotein efflux pump. Both factors lead to its low oral bioavailability (48%). The daily dose of AMS is between 200 and 1200mg to be taken in divided doses which compromise patient compliance. Therefore, controlled release formulation of AMS is of clinical significance. AMS was formulated into matrix tablets containing Labrasol, P-glycoprotein efflux inhibitor, and a penetration enhancer, using direct compression technique. The tablets were prepared according to 21·41 factorial design using two polymers, namely, HPMC and Carbopol 934 at four concentrations (20%, 30%, 40%, 50%). Percentage AMS released after 2h (Q2hr%) and 8h (Q8hr%) were chosen as dependent variables. Two acidic pH modifiers (fumaric acid and tartaric acid) at two levels (15% and 30%) were incorporated in the tablet according to 22 factorial design. All formulae with acidic pH modifier had similarity factor (f2) ≥ 50 proving the pH independent release of AMS. The pharmacokinetic study in rabbits revealed 30% enhancement of the oral absorption AMS imparted by the pH-modified matrix tablet containing Labrasol. Graphical abstract.

Preparation and in vitro evaluation of Chondroitin sulfate and carbopol based mucoadhesive controlled release polymeric composites of Loxoprofen using factorial design

Drug delivery systems based upon combination of natural and synthetic polymers are considered as stable formulations with promising release characteristics. In current research work, Chondroitin sulfate (Natural), Carbopol-934 (Synthetic) and 2-Acrylamido-2-methylpropane sulfonic based semi-interpenetrating hydrogels were synthesized through free radical polymerization technique using Ethylene Glycol Dimethylacrylate as a cross linker. Nine formulations with different concentrations of Chondroitin sulfate and Carbopol-934 were prepared. Structural and morphological characterization was accomplished by using SEM, FTIR, DSC, TGA and XRD. Chemical evaluation was carried out to explore pH independent swelling characteristics, porosity, drug entrapment efficiency, bioadhesive strength and in-vitro drug release behavior. Results were then statistically analyzed and optimum formulation was selected by using numerical approach of 32 factorial design. Results confirmed the formation of stable and firm hydrogel formulation with pH independent and controlled release of Loxoprofen sodium. These hydrogel formulations can be used as suitable alternative to conventional drug delivery systems to achieve optimum therapeutic outcomes.

In vitro and in vivo assessment of Adansonia digitata mucilage as a matrix former in modified release tablets of metoprolol tartrate

The study was aimed to investigate the ability of Adansonia digitata mucilage (ADM) a new hydrophilic plant polymeric material, in modifying metoprolol tartrate (MPT) release from matrix tablet formulations in comparison with a semi -synthetic polymer-HPMC60SH 4000. Modified release tablets of MPT were directly compressed in the ratios of 1:1 and 1:4 drug/polymer amounts. The tablets properties were evaluated and further, in vivo studies were carried out on 1:4 drug/polymer matrix tablets formulated with ADM and compared with Slow- Lopressor Divitab®. In vitro drug release of MPT was controlled over 24 h for tablets with 1:4 drug/polymer ratios. Release profiles of formulations showed pH independent release and no burst effect at high drug loading. Matrix integrity was maintained throughout dissolution with ADM matrices, an indication of good gel strength contrary to HPMC matrices. Statistical analysis confirmed that MPT release from ADM and HPMC (1:4 drug/polymer) was not significantly different (P > 0.05) likewise similarity factor (f2). The in vivo bioavailability after oral administration of the test formulation (1:4 MPT/ADM) to dogs did not differ significantly from the reference marketed sustained release product.

Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize permeability of captopril oral films

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.

Effect of melt extrudability and melt binding efficiency of polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®) on release pattern of hydrophilic and high dose drugs

The present study explores the effect of melt binding of Soluplus® on in vitro release profiles of two hydrophilic drugs, metformin hydrochloride, and paracetamol. The melt viscosities of bulk polymer and physical mixtures with different concentrations of selected APIs were analyzed by using a rheometer. The rheological evaluation revealed both the suitable temperature range for melt extrusion process and drug-polymer extrudability. The effect of formulation and processing parameters (e.g. polymer/drug ratio, temperature, screw speed) on extrudability were evaluated in terms of torque and residence time analysis. The extrudates obtained via hot melt extrusion (HME) processing exhibited good flow and compressibility. Differential scanning calorimetry (DSC) and X-ray diffraction studies examined the change in glass transition temperature (Tg) and crystalline pattern of extruded formulations where all extruded formulations seemed to have retained their crystallinity. The thermogravimetric analysis determined the thermal stability (weight loss) as a function of operating temperature whereas scanning electron microscopy (SEM) showed agglomerated microstructure and rough surface with a porous network and void spaces. The tablets obtained after compression of milled extrudates showed excellent hardness with robust tablet characteristics. The in vitro release studies of individual batches performed in various USP recommended dissolution media (for paracetamol) showed the pH-independent release of the hydrophilic drugs from the polymer matrices.

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.

Development of pH Independent Drug Release System for Dipyridamole

Abstract: Introduction: Dipyridamole is an Anti-platelet agent exhibits release problems at higher pH of small intestine due to its pH dependent solubility and precipitation followed by interruption of drug release from dosage form. To overcome this extended release formulation was developed by using pH modulating agent (tartaric acid). Objective: Present study was undertaken with a view of the formulations evaluated by performing dissolution testing on developed extended released tablets. Method: development of dissolution method at different time points and USP Apparatus 1 (basket) and 2 (paddle) at rotating speeds of 50 or 100 rpm used to evaluate the release characteristics of the formulations. Furthermore, solubility and in vitro dissolution studies of formulated tablets were performed at pH values of 1.2 and 5.5. Results: In this study we found increasing volume of dissolution medium pH 5.5 phosphate buffers drug precipitation is increased. The developed dissolution method was validated according to ICH guidelines for various parameters such as specificity, accuracy, precision, and stability. The dissolution method was confirmed by determining the dissolution rate of extended released Dipyridamole tablets containing pH modulating agent. The best in vitro dissolution profile was obtained using pH 5.5 phosphate buffer as the dissolution medium (500 ml) stirred at 100 rpm. A comparison of the dissolution profiles in official and developed media showed significant differences based on f1 and f2 values. Conclusoni: The developed dissolution test exhibited a higher capacity than the compendia methods in differentiating the release profiles of pH independent extended release tablets. It can be applied during formulation development and quality control analysis of pH independent extended release tablets for evaluation of the effects of pH modifier in dissolution medium and processing parameters. Key words: Tartaric acid, Dissolution media, Extended release Dipyridamole Tablets.

Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug

The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH6.8 and pH1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24h in acidic media (pH1.2). The release profile in acidic media was similar to the alkaline media (pH6.8) with a similarity factor (f2) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile.

Matrix Tablet Containing Quaternary Inclusion Complex of Domperidone for Treatment of Diabetic Gastroparesis

Abstract: Objective: The present investigation is aimed at development and optimization of a pH independent controlled release matrix tablet containing mannitol based quaternary inclusion complex (QIC) of domperidone (DOM) for the treatment of diabetic gastroparesis. Methods: The tablets were prepared by direct compression and central composite design was used to optimize the amount of sodium alginate (SA) and hydroxypropylmethylcellulose (HPMC) to obtain a final formulation with desired release characteristics. The drug release from the optimized formulation was compared with the tablets containing pure DOM, binary and ternary inclusion complexes. Results and Discussion: The formulations showed a zero order release profile. The design models suggested greater influence of SA on the drug release. The optimized formulation showed minimum burst effect and released 88.65±3.19% DOM at the end of 12 h. The comparative study revealed that the optimized formulation exhibited nearly complete release of DOM. Conclusion: It was concluded that the optimized formulation containing QIC may reduce the dose frequency and improve the bioavailability of DOM. Key words: Quaternary inclusion complex, pH independent controlled release, Domperidone, Central composite design, Diabetic gastroparesis.

Studies on Solubility Enhancement of Poorly Soluble NSAID Using Dual Approach of Micro-environmental pH Modulation and Melt Granulation.

The present work describes the role of melt granulation and microenviron-mental pH modulation technique in solubility enhancement of a poorly water soluble NSAID, Aceclofenac (ACL). ACL is a BCS Class II drug showing dissolution rate limited absorption and pH dependent solubility, with higher solubility at alkaline pH. The limited solubility of ACL affects drug absorption and hence, therapeutic effect as the drug is indicated in conditions of pain where rapid onset of action is desired. Solubility enhancement of ACL was carried out by melt granulation technique using Gelucire 50/13 as molten carrier. The solubility of ACL was improved further by incorporating sodium hydrogen carbonate as pH modifier. The granules of ACL thus developed, were compressed into tablets using adsorbing carriers and other tableting excipients. This dual approach not only enhanced ACL solubility but also aided in achieving a pH independent release. The developed tablets exhibited pH independent release as well as enhanced rate of dissolution which is indicated by in vitro dissolution studies and ex-vivo intestinal permeation studies. The pH independent release would ensure absorption of drug throughout the gastrointestinal tract. The solubility enhancement of ACL was further confirmed by characterization studies such as DSC and XRD. Thus, the dual approach of melt granulation and micro-environmental pH modulation can be simple and scalable method for solubility enhancement of poorly soluble drugs showing pH dependent dissolution rate limited absorption.