Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis.

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm.2018 and Bermejo, et al. M. Mol. Pharm.2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pKa) and its interplay with the pH modifier pKa or pKas. As an example of this complex interaction, for basic drugs with high pKa and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pKa, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

Relative Bioavailability Risk Assessment: A Systematic Approach to Assessing In Vivo Risk Associated With CM&C-Related Changes.

Relative bioavailability (RBA) studies are often carried out to bridge changes made between drug products used for clinical studies. In this work, we describe the development of a risk assessment (RA) tool that comprehensively and objectively assesses the risk of noncomparable in vivo performance associated with Chemistry, Manufacturing, and Controls (CM&C)-related changes. The RA tool is based on a risk grid that provides a quantitative context to facilitate discussions to determine the need for an in vivo RBA study. Relevant regulatory guidances and the required in vitro and in silico absorption modeling data, on which the RA is based, are discussed. In addition, an analysis of previously executed RBA studies at Eli Lilly and Company over a period of several years is presented. The risk grid incorporates individual risk factors for a given study and provides a recommendation on the risk associated with bypassing an RBA study. The outcome of an RA results in 1 of 3 possible risk zones; lower tier risk, intermediate tier risk, and upper tier risk. In cases where the outcome from the RA falls into the intermediate tier risk zone, further in depth data analysis is required.

FIP Guidelines for Dissolution Testing of Solid Oral Products.

Dissolution testing is an important physiochemical test for the development of solid oral dosage forms, tablets, and capsules. As a quality control test, the dissolution test is used for assessment of drug product quality and is specified for batch release and regulatory stability studies. In vitro dissolution test results can often be correlated with the biopharmaceutical behavior of a product.This article provides a summary of views from major global agencies (Europe, Japan, United States), pharmacopoeias, academia, and industry. Based on available guidance and literature, this article summarizes highlights for development and validation of a suitable dissolution method, setting appropriate specifications, in vitro-in vivo comparison, and how to obtain a biowaiver.

Development of an in vivo-relevant drug product performance method for an amorphous solid dispersion.

The purpose of this work was to develop a meaningful in vitro dissolution method for evacetrapib spray-dried dispersion (SDD) tablets that is discriminating for crystalline drug substance (DS) content. Justification of the method conditions included evaluation of dissolution media, rotation speed, surfactant selection and level of surfactant to achieve sink conditions. Discrimination was illustrated by testing SDD tablets spiked with 10%, 20%, and 30% crystalline DS. The results demonstrated a 13%, 22% and 32% drop in the dissolution end point, respectively, as compared to unspiked SDD tablets. Additionally, tablets containing crystalline DS and tablets containing SDD were tested in a relative bioavailability (RBA) study. Utilizing the proposed dissolution method, the dissolution end point of SDD tablets was determined to be approximately 4 fold higher than that of the tablets containing crystalline DS. These results compare favourably to the in vivo RBA study results where SDD tablets had a 4.6 fold increase in exposure compared to tablets containing crystalline DS.

Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug.

Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model.

An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation.

Characterization of a novel cross-linked lipase: impact of cross-linking on solubility and release from drug product.

Liprotamase is a novel non-porcine pancreatic enzyme replacement therapy containing purified biotechnology-derived lipase, protease, and amylase together with excipients in a capsule formulation. To preserve the structural integrity and biological activity of lipase (the primary drug substance) through exposure of the drug product to the low-pH gastric environment, the enzyme was processed through the use of cross-linked enzyme crystal (CLEC) technology, making the lipase-CLEC drug substance insoluble under acidic conditions but fully soluble at neutral pH and in alkaline environments. In this report we characterize the degree of cross-linking for lipase-CLEC and demonstrate its impact on lipase-CLEC solubility and release from the drug product under relevant physiological pH conditions. Cross-linked lipase-CLEC was characterized via size exclusion chromatography (SEC) and capillary electrophoresis sodium dodecyl sulfate polyacrylamide gel electrophoresis (CE-SDS-PAGE). A combination of methodologies was developed to understand the impact of cross-linking on drug product release. Dissolution evaluation using USP Apparatus 2 at pH 5.0 with an enzyme activity-based end point demonstrated solubility discrimination based on degree of cross-linking, while full release was demonstrated at pH 6.5. The dissolution of the drug product was also evaluated using a dual-stage test employing a USP Apparatus 4 flow-through system to mimic the changing pH environments experienced in the stomach and intestine to understand the impact of cross-linking on drug product performance. Use of USP Apparatus 4 to characterize the pH-dependent release of lipase-CLEC represents a novel approach compared to the Apparatus 1 test employing an acid-challenge stage outlined in the USP for delayed-release pancrelipase, and the advantages of this approach may prove useful for understanding the pH-dependence of release for other drug products. Collectively, these studies confirmed that degree of cross-linking is a critical parameter that may impact in vivo release of lipase-CLEC, and also provided a risk assessment tool for understanding the potential impact of under- and over-cross-linked drug substance.

Optimization of LY545694 tosylate controlled release tablets through pharmacoscintigraphy.

PURPOSE: To optimize a controlled release (CR) matrix formulation with two goals: (1) effectively deliver a prodrug to a preferred absorption region of the upper GI tract, and (2) afford a PK profile similar to a "reference" CR formulation. METHODS: A pharmacoscintigraphic clinical study was conducted using a flexible formulation design space. A six-arm, three-prototype study was employed to cover the formulation design space and assess performance against the reference formulation. Pharmacokinetic and scintigraphic data from the first three dosing arms were used to select prototypes to be dosed in subsequent arms. RESULTS: Of three prototypes tested, the third prototype had an optimal release rate. The in vivo erosion rate was observed via scintigraphy to reach 90% in 3 h. The AUC ratio relative to the reference for the prodrug was 1.25, while the C(max) ratio was 1.07. The ratios for the active moiety were 1.31 (AUC) and 1.01 (C(max)). CONCLUSIONS: A single pharmacoscintigraphic study efficiently investigated a wide formulation design space and precisely optimized the release rate with few formulation iterations. The selected formulation provided the desired exposure at a 30% lower dose. The approach is beneficial when drug absorption is limited to a region of the GI tract.

Dissolution modeling of bead formulations and predictions of bioequivalence for a highly soluble, highly permeable drug.

The objective of this study was to assess the impact of observed in vitro dissolution rate differences on in vivo pharmacokinetics for two enteric-coated bead formulations of a highly soluble, highly permeable drug. A new bead dissolution model was developed to quantitatively simulate the dissolution profiles of the two formulations. The model is based on the boundary layer diffusion model and can be used to simulate dissolution profiles for bead formulations using physicochemical properties of the formulation. The model was applied to show that the observed differences in dissolution profiles can be attributed completely to the difference in surface area of the beads for the two formulations. An absorption/pharmacokinetic model (GastroPlus) was used to predict the in vivo plasma concentration time profiles for the formulations using their respective in vitro dissolution profiles as input. The simulation results showed that the plasma concentration-time profiles were not significantly impacted by slower dissolution rates. Additionally, a sensitivity analysis was performed with a range of dissolution rate profiles. The fastest dissolution rate reached 80% dissolved in 41 min, while the slowest reached 80% in 114 min. Over this range, the predicted C(max) decreased by 9% and the AUC decreased by 1%. An in vivo bioequivalence study on the two experimental formulations demonstrated the formulations were bioequivalent, consistent with predictions. The lack of sensitivity is attributable to the high permeability and long elimination half-life of the drug. The work presented in this article demonstrates the use of a bead dissolution model and an absorption/PK model to predict in vivo formulation performance.

In vitro monitoring of dissolution of an immediate release tablet by focused beam reflectance measurement.

Changes in in vitro drug release profiles of oral dosage forms are commonly observed due to storage of drug product at elevated temperature and humidity. An example is presented of an immediate release drug product which underwent changes to both release profile and crystal form on storage at elevated humidity. The dissolution rate for unstressed tablets was comparable regardless of the crystal form present. Decreased release rate was only observed for stressed tablets that exhibited crystal form conversion. The cause of the dissolution change was determined by evaluating tablets manufactured with three drug substance crystal forms by fiber optic ultraviolet detection and focused beam reflectance measurement (FBRM). Tablets were also analyzed by near-infrared spectroscopy for crystal form determination. The observed change in dissolution rate correlated with detection of a greater number of larger particles by FBRM. FBRM results indicate increased aggregation of the tablet material due to crystal form conversion, resulting in the presence of slowly disintegrating and dissolving granules during the dissolution process. The improved understanding of the dissolution process allows evaluation of the potential in vivo impact of the stability changes.

Use of artificial stomach-duodenum model for investigation of dosing fluid effect on clinical trial variability.

Lilly Compound X (LCX) is an oncology drug that was tested in a phase I clinical study using starch blend capsules. The drug was given to a small patient population (4 patients) and showed large inter- and intra-patient variability. In order to evaluate the possible effect of stomach pH on exposure and ways to mitigate the variability issue, artificial stomach-duodenum (ASD) experiments were conducted to investigate the hypothesis that carefully selected dosing fluids would have an impact in minimizing exposure variability caused by the formulation, which could lead to more consistent evaluation of drug absorption in patients. The ASD data corroborates the observed variability, and was a good tool to investigate the effect of stomach pH and potential dosing solutions on duodenal concentrations. Administering capsules co-formulated with Captisol (10% drug load) along with Sprite was shown by the ASD to be an effective way to increase duodenal concentrations as well as to reduce the difference between duodenal concentrations for different gastric pH. The reduction in variability of duodenum AUC (in ASD) is expected to correlate well with a reduction of variability in patient exposure. The dosing regimen of Sprite/Captisol is therefore suggested for future clinical trials involving LCX. Furthermore, for design of early phase clinical trials, ASD technology can be used to assist in choosing the proper dosing solution to mitigate absorption and exposure variability issues.

Relative bioavailability of three different solid forms of PNU-141659 as determined with the artificial stomach-duodenum model.

The artificial stomach-duodenum (ASD) apparatus was designed and constructed to assess the in vitro performance of bulk drugs and their formulations in a device which is able to simulate different species and physiological conditions. As a continued demonstration of its application to a pharmaceutical problem, screening experiments were performed on three different solid forms of a drug candidate, PNU-141659. This compound exhibited poor solubility and permeability, and presented a significant problem in the development of a successful dosage form. Simple formulations of an anhydrous form, a hydrated form and an amorphous form of the drug were all assessed with the ASD set up to simulate dog physiology. The solubility ordering of these three forms was anhydrate < hemihydrate < amorphous and this is the first ASD study to directly compare amorphous and crystalline solid forms. However, the results of the ASD studies showed that the hydrated form, with the intermediate solubility should provide the highest bioavailability, not the more soluble amorphous form. This occurred because the more soluble amorphous form underwent a phase conversion to Form I during the ASD experiment. The results from the ASD compared favorably with those later obtained from in vivo dog studies.

Development of a rapidly dispersing tablet of a poorly wettable compound: formulation DOE and mechanistic study of effect of formulation excipients on wetting of celecoxib.

Celecoxib has extremely poor aqueous wettability and dispersibility. A dispersibility method was developed to study the effects of formulation excipients and processing methods on wetting of celecoxib. In this method, a tablet or powder was placed in water and the turbidity of the resulting "dynamic" suspension was measured. Higher turbidity values reflect better dispersibility. Results show that wet granulation facilitates better drug dispersion than does dry granulation or direct compression. Results from a screening formulation statistical design of experiments (DOE) show that sodium lauryl sulfate (SLS), an anionic surfactant, gives higher celecoxib dispersibility than polysorbate 80, a neutral surfactant. Polyplasdone XL as a disintegrant results in better celecoxib dispersibility than sodium starch glycolate. The binder Kollidon 30 leads to better dispersibility, but slower disintegration than Kollidon 12. Jet-milling celecoxib with excipients not only improves dispersibility of the drug but also the ease of material handling. The method of microcrystalline cellulose addition does not significantly impact tablet properties. The effect of critical formulation variables on the wettability of celecoxib was further examined in prototype formulations. It is found that ionic surfactant resulted in better dispersibility than a neutral surfactant, probably due to charge dispersion. Kollidon 30 gives better drug dispersion than hydroxypropylmethyl cellulose and hydroxypropyl cellulose. This may be explained through a surface energy calculation, where the spreading coefficients between Kollidon 30 and celecoxib indicate formation of open porous granules in which pores can facilitate water uptake. The mode of disintegrant addition also impacts dispersibility of the drug. Dense granules were formed when the disintegrant, Polyplasdone, was added intra-granularly. As the extra-granular portion of the disintegrant increases, the dispersibility of the drug increases as well. The drug initial dispersibility (turbidity at 5 min during the dispersibility test) increases as the tablet porosity increases. A 3-factor face-centered experimental design was conducted to optimize the levels of surfactant (SLS), binder (Kollidon 30) and disintegrant (Polyplasdone). Within the range that was studied, the dispersibility of micronized drug increases as the amount of SLS and Kollidon 30 increases. The level of Polyplasdone has no significant impact on the dispersibility of micronized drug; however, higher levels of Polyplasdone lead to significantly harder tablets.

Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model.

The in vitro dissolution of carbamazepine (CBZ) was investigated using an automated artificial stomach-duodenum (ASD) model. Successful simulation of the dog physiology in the fasted state showed that the rank order of the ASD estimated bioavailabilities is as follows: Form III > Form I > dihydrate. This result is in excellent agreement with those found in literature. Additional simulations comparing different gastric transit times during fasted and fed states are also discussed.

Spectroscopy and reactivity of size-selected Mg+ -ammonia clusters.

Photodissociation spectra for mass-selected Mg(+)(NH(3))(n) clusters for n=1 to 7 are reported over the photon energy range from 7000 to 38 500 cm(-1). The singly solvated cluster, which dissociates primarily via a N-H bond cleavage, exhibits a resolved vibrational structure corresponding to two progressions in the intracluster Mg(+)-NH(3) modes. The addition of the second, third, and fourth solvent molecules results in monotonic redshifts that appear to halt near 8500 cm(-1), where a sharp feature in the electronic spectrum is correlated with the formation of a Mg(+)(NH(3))(4) complex with T(d) symmetry and the closing of the first solvation shell. The spectra for the clusters with 5 to 7 solvent molecules strongly resemble that for the tetramer, suggesting that these solvent molecules occupy a second solvation shell. The wavelength-dependent branching-ratio measurements show that increasing the photon energies generally result in the loss of additional solvent molecules but that enhancements for a specific solvent number loss may reveal special stability for the resultant fragments. The majority of the experimental evidence suggests that the decay of these clusters occurs via the internal conversion of the initially excited electronic states to the ground state, followed by dissociation. In the case of the monomer, the selective cleavage of a N-H bond in the solvent suggests that this internal-conversion process may populate regions of the ground-state surface in the vicinity of an insertion complex H-Mg(+)-NH(2), whose existence is predicted by ab initio calculations.