Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions?

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a weakly acidic polymer that is widely used in the formulation of amorphous solid dispersions (ASDs). While the pH-dependent solubility of HPMCAS is widely recognized, the role of other solution properties, including buffer capacity, is less well understood in the context of ASD dissolution. The goal of this study was to elucidate the rate-limiting steps for drug and HPMCAS release from ASDs formulated with two poorly water soluble model drugs, indomethacin and indomethacin methyl ester. The surface area normalized release rate of the drug and/or polymer in a variety of media was determined. The HPMCAS gel layer apparent pH was determined by incorporating pH sensitive dyes into the polymer matrix. Water uptake extent and rate into the ASDs were measured gravimetrically. For neat HPMCAS, the rate-limiting step for polymer dissolution was observed to be the polymer solubility at the polymer-solution interface. This, in turn, was impacted by the gel layer pH which was found to be substantially lower than the bulk solution pH, varying with medium buffer capacity. For the ASDs, the HPMCAS release rate was found to control the drug release rate. However, both drugs reduced the polymer release rate with indomethacin methyl ester having a larger impact. In low buffer capacity media, the presence of the drug had less impact on release rates when compared to observations in higher strength buffers, suggesting changes in the rate-limiting steps for HPMCAS dissolution. The observations made in this study can contribute to the fundamental understanding of acidic polymer dissolution in the presence and absence of a molecularly dispersed lipophilic drug and will help aid in the design of more in vivo relevant release testing experiments.

Harmonizing Biopredictive Methodologies Through the Product Quality Research Institute (PQRI) Part I: Biopredictive Dissolution of Ibuprofen and Dipyridamole Tablets.

Assessing in vivo performance to inform formulation selection and development decisions is an important aspect of drug development. Biopredictive dissolution methodologies for oral dosage forms have been developed to understand in vivo performance, assist in formulation development/optimization, and forecast the outcome of bioequivalence studies by combining them with simulation tools to predict plasma profiles in humans. However, unlike compendial dissolution methodologies, the various biopredictive methodologies have not yet been harmonized or standardized. This manuscript presents the initial phases of an effort to develop best practices and move toward standardization of the biopredictive methodologies through the Product Quality Research Institute (PQRI, https://pqri.org ) entitled "The standardization of in vitro predictive dissolution methodologies and in silico bioequivalence study Working Group." This Working Group (WG) is comprised of participants from 10 pharmaceutical companies and academic institutes. The project will be accomplished in a total of five phases including assessing the performance of dissolution protocols designed by the individual WG members, and then building "best practice" protocols based on the initial dissolution profiles. After refining the "best practice" protocols to produce equivalent dissolution profiles, those will be combined with physiologically based biopharmaceutics models (PBBM) to predict plasma profiles. In this manuscript, the first two of the five phases are reported, namely generating biopredictive dissolution profiles for ibuprofen and dipyridamole and using those dissolution profiles with PBBM to match the clinical plasma profiles. Key experimental parameters are identified, and this knowledge will be applied to build the "best practice" protocol in the next phase.

Current State and Opportunities with Long-acting Injectables: Industry Perspectives from the Innovation and Quality Consortium "Long-Acting Injectables" Working Group.

Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval.

Food effect risk assessment in preformulation stage using material sparing µFLUX methodology.

The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state.

Using Tiny-TIM Dissolution and In Silico Simulation to Accelerate Oral Product Development of a BCS Class II Compound.

Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro-in vivo correlation and to predict the oral bioavailability. The level C in vitro-in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro-in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process.

Prediction of in vivo supersaturation and precipitation of poorly water-soluble drugs: Achievements and aspirations.

This review focuses on options available to a pharmaceutical scientist to predict in vivo supersaturation and precipitation of poorly water-soluble drugs. As no single device or system can simulate the complex gastrointestinal environment, a combination of appropriate in vitro tools may be utilized to get optimal predictive information. To address the empirical issues encountered during small-scale and full-scale in vitro predictive testing, theoretical background and relevant case studies are discussed. The practical considerations for selection of appropriate tools at various stages of drug development are recommended. Upcoming technologies that have potential to further reduce in vivo studies and expedite the drug development process are also discussed.

Effect of processing conditions and excipients on dehydration kinetics of sodium naproxen hydrate in formulation.

The manufacture of oral dosage form may induce changes in the physical form of an active pharmaceutical ingredient. One such example includes formation of hydrate during granulation followed by the reverse transition to the anhydrous form during drying. We used naproxen sodium dihydrate (DH) as the model compound and studied its dehydration at elevated temperature under different processing conditions, (i) in ambient air, (ii) in flow of inert gas (iii) under low pressure environment, and (iv) under 'high' pressure in closed environments. In situ variable temperature X-ray diffraction was used to monitor kinetics of phase transformation under these processing conditions. The DH dehydration was fastest under the flow of inert gas and slowest in closed environment. Polyvinyl pyrrolidone (PVP) and microcrystalline cellulose (MCC), commonly used hygroscopic solids, were used as the model excipients to monitor influence of excipients in modulating DH dehydration behavior under different processing conditions. Both the excipients altered the kinetics as well as the extent of DH dehydration, with PVP delaying and MCC facilitating the transformation under all processing conditions studied. The results indicate that the physical form of API, such as hydrate or anhydrous in the present case, in the formulation may be modulated by rational excipient selection.

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies.

Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.

Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations.

Since the discovery of X-ray diffraction and its potential to elucidate crystal symmetry, powder X-ray diffraction has found diverse applications in the field of pharmaceutical sciences. This review summarizes significant achievements of the technique during various stages of dosage form development. Improved understanding of the principle involved and development of automated hardware and reliable software have led to increased instrumental sensitivity and improved data analysis. These advances continue to expand the applications of powder X-ray diffraction to emerging research fields such as amorphous systems, mechanistic understanding of phase transformations, and "Quality by Design" in formulation development.