Microenvironmental pH Modulation Research Articles

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.

We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

The Degradation Chemistry of GSK2879552: Salt Selection and Microenvironmental pH Modulation to Stabilize a Cyclopropyl Amine

The cyclopropyl amine moiety in GSK2879552 (1) degrades hydrolytically in high pH conditions. This degradation pathway was observed during long-term stability studies and impacted the shelf life of the drug product. This article describes the work to identify the degradation impurities, elucidate the degradation mechanism, and design a stable drug product. It was found that salt selection and control of the microenvironmental pH of the drug product formulation blend significantly improved the chemical stability of the molecule in the solid state.

Dual mechanism of microenvironmental pH modulation and foam melt extrusion to enhance performance of HPMCAS based amorphous solid dispersion

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is an excellent polymeric carrier for melt extrusion amorphous solid dispersion. However, its pH-dependent solubility limits its application, especially for narrow absorption window drugs. The current study proposed a novel dual approach of foam extrusion and microenvironmental pH modulation to overcome this limitation. Sodium bicarbonate was used as a blowing agent and the remaining sodium carbonate acted as an internal pH modifier. Compared with conventional extrusion, foam extrusion dramatically lowered the extrudate physical strength (breaking force and hardness decreased by 20-fold; breaking energy and deformation energy decreased by >30-fold). Milling efficiency of foam extrudate was largely improved compared with that of conventional extrudates, demonstrating smaller particle size, larger specific surface area, and ability to pass through a smaller milling screen. The foam extrudate could generate a supersaturation concentration up to 8-fold higher than the solubility of the pure drug. It also significantly enhanced drug dissolution in a two-step biorelevant medium (p < 0.05). This novel approach improved both manufacturing processability and dissolution of HPMCAS-based solid dispersions.

Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid - Case Study of GDC-0810.

The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human. The pH-solubility profile of GDC-0810 free acid and pHmax of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810 NMG salt at different pH values. GDC-0810 200-mg dose NMG salt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food. Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pHmax of the NMG salt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of Cmax and AUC0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant. Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.

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.

Enhanced gastric stability of esomeprazole by molecular interaction and modulation of microenvironmental pH with alkalizers in solid dispersion

Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pHM) was measured to evaluate the effect of the alkalizer on the pHM of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer-containing SD and the enteric-coated reference tablet Nexium® were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pHM values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pHM values decreased in the following order: MgO, Na2CO3, Ca(OH)2, and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium® and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method.

Modulation of microenvironmental pH for dual release and reduced in vivo gastrointestinal bleeding of aceclofenac using hydroxypropyl methylcellulose-based bilayered matrix tablet

This study was designed to develop a once-daily controlled-release matrix tablet of aceclofenac 200mg (AFC-CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC-CR tablets were carried out in simulated intestinal fluid (pH6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate-release reference tablet Airtal® 100mg (Daewoong Co., Korea) and the optimized AFC-CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC-CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near-infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na2CO3) was found to enhance the release rate of the AFC-CR bilayered tablets at early stages and increase the microenvironmental pH (pHM). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained-release pattern for the AFC-CR tablet compared to the Airtal® tablet. AFC-CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC-CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pHM of drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled-release matrix tablet with enhanced patient compliance and better pain control.

Modulation of microenvironmental pH and utilization of alkalizers in crystalline solid dispersion for enhanced solubility and stability of clarithromicin.

Clarithromycin (CAM) is known to be poorly water-soluble and acid-labile drug. Various alkalizers such as MgO, Na2CO3, Na2HPO4 and NaHCO3 were utilized to modulate the microenvironmental pH (pHM) and to improve the low stability and solubility of CAM in a crystalline-solid dispersion system (CSD). Polyvinylpyrrolidone (PVP K-30) and hydroxypropylmethylcellulose (HPMC) 4000-based CSDs containing alkalizers were prepared by cosolvent precipitation followed by evaporation process. The dried-CSDs mixed with microcrystalline cellulose, 2% croscarmellose sodium, and 1% magnesium stearate was then directly compressed into tablet. A dissolution test was carried out in 900 mL of pH 5.0 buffer solutions at 37 °C with a 50 rpm paddle speed. pHM, surface morphology, and structural behaviors were investigated. The dissolution rates of CAM in CSD containing alkalizers were improved. The drug in CSD remained crystalline as observed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy revealed nearly identical images regardless of the sorts and amounts of carriers. PVP-based CSD tablet without alkalizer showed greater drug release, while HPMC-based CSD tablet without alkalizer retarded drug release due to its greater swelling capability. However, when the alkalizers were added in CSD tablet, the drug release was sharply increased. NaHCO3 induced the most rapid drug release while MgO retarded drug dissolution. Alkalizers in CSD also could maintain the pHM of the tablet above pH 5 under acidic conditions. The use of pH modifiers in CSDs could provide a useful method to improve the dissolution rate and stability of CAM via modulation of pHM without changing drug crystallinity.

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.

Erratum to: Enhancing and Sustaining AMG 009 Dissolution from a Matrix Tablet Via Microenvironmental pH Modulation and Supersaturation

Erratum to: Enhancing and Sustaining AMG 009 Dissolution from a Matrix Tablet Via Microenvironmental pH Modulation and Supersaturation

Enhancing and Sustaining AMG 009 Dissolution from a Matrix Tablet Via Microenvironmental pH Modulation and Supersaturation

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Evaluation of the deformation behavior of binary systems of methacrylic acid copolymers and hydroxypropyl methylcellulose using a compaction simulator

Methacrylic acid copolymers have been shown to enhance release of weakly basic drugs from rate controlling polymer matrices through the mechanism of microenvironmental pH modulation. Since these matrices are typically formed through a compaction process, an understanding of the deformation behavior of these polymers in there neat form and in combination with rate controlling polymers such as HPMC is critical to their successful formulation. Binary mixes of two methacrylic acid copolymers, Eudragit ® L100 and L100-55 in combination with HPMC K4M were subjected to compaction studies on a compaction simulator. The deformation behavior of the powder mixes was analyzed based on pressure–porosity relationships, strain rate sensitivity (SRS), residual die wall force data and work of compaction. Methacrylic acid copolymers, L100-55 and L-100 and the hydrophilic polymer, HPMC K4M exhibited Heckel plots representative of plastic deformation although L-100 exhibited significantly greater resistance to densification as evident from the high yield pressure values (∼120 MPa). The yield pressures for the binary mixes were linearly related to the weight fractions of the components. All powder mixes exhibited significant speed sensitivity with SRS values ranging from 21.7% to 42.4%. The residual die-wall pressures indicated that at slow speeds (1 mm/s) and at lower pressures (<150 MPa), HPMC possesses significant elastic behavior. However, the good compacts formed at this punch speed indicate significant plastic deformation and bond formation which is able to predominate over the elastic recovery component. The apparent mean yield pressure values, the residual die-wall forces and the net work of compaction exhibited a linear relationship with mixture composition, thereby indicating predictability of these parameters based on the behavior of the neat materials.

Microenvironmental pH Modulation Based Release Enhancement of a Weakly Basic Drug from Hydrophilic Matrices

For weakly basic drugs, pH-dependent solubility characteristics can translate into low and incomplete release of these drugs from sustained release formulations. The objective of this study was to quantitatively analyze the relationship between microenvironmental pH modulation and release enhancement of a weakly basic drug in the free base form. A prototype matrix system primarily consisting of trimethoprim (pK(a) 6.6), hydroxypropyl methylcellulose (HPMC), and a polymeric or nonpolymeric pH modulator was used. Incorporation of the methacrylic acid polymer, Eudragit L100-55 resulted in marginal release enhancement as the pH modulation effected by this polymer was attenuated by the basicity of the drug. Water uptake and scanning electron microscopy (SEM) studies suggested that Eudragit L100-55 incorporation also resulted in reduced water uptake and matrix permeability. The effect of nonpolymeric pH modulators on release enhancement was also studied. The lowering in microenvironmental pH by malic acid was sufficiently high and persistent to result in pH-independent release. A correlation plot between the experimentally determined microenvironmental pH, effected by the polymeric and nonpolymeric pH modulators, and percent drug release, exhibited good linearity with a correlation coefficient of 0.83; thereby, indicating that drug diffusion across the gel barrier is the predominating mechanism of release.