Some observations on the liquid crystalline and gel behaviors of aqueous dispersions of a prodrug.

BMS-830216 is a diprotic acid prodrug of two pKa values (<2 and 6.8) with high apparent solubility at pH ≥ 7. At ∼ pH 4 solutions of BMS-830216 appear to be surface active, in which their surface tension can be reduced from 72 to 65 dynes when its concentrations is above the critical aggregation concentration (CAC∼0.2 mM). Additionally, at this pH, BMS-830216 tends to form liquid crystalline phases (at ≥ 2 mg/mL) in acetate buffer when using tris salt. Furthermore, after raising the concentration beyond 20 mg/g, formation of gel-like dispersions was noted. These gel-like dispersions exhibited a strong elastic strength, significantly impacting the dissolution behavior of the tris salt. Mechanistically, it is likely that BMS-830216 tris salt in solution first forms a lamellar phase followed by formation of a gel phase at higher concentrations (≥20 mg/mL). As indicated by SAXS, the lamellar phase formed seems to have two d-spacing values (∼5 nm and ∼10 nm (weak), which seems to correspond to two molecules connected tail by tail (5 nm). Further investigation is needed for phase identification, as their properties can affect the physical behavior of BMS-830216 in the development of pharmaceutical dosage forms.

Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug.

PURPOSE: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated. METHODS: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables. RESULTS: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data. CONCLUSIONS: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

The effect of polymeric excipients on the physical properties and performance of amorphous dispersions: Part I, free volume and glass transition.

PURPOSE: To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition. METHODS: Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions. RESULTS: The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution. CONCLUSIONS: Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy.

Weak base therapeutic agents can show reduced absorption or large pharmacokinetic variability when coadministered with pH-modifying agents, or in achlorhydria disease states, due to reduced dissolution rate and/or solubility at high gastric pH. This is often referred to as pH-effect. The goal of this study was to understand why some drugs exhibit a stronger pH-effect than others. To study this, an API-sparing, two-stage, in vitro microdissolution test was developed to generate drug dissolution, supersaturation, and precipitation kinetic data under conditions that mimic the dynamic pH changes in the gastrointestinal tract. In vitro dissolution was assessed for a chemically diverse set of compounds under high pH and low pH, analogous to elevated and normal gastric pH conditions observed in pH-modifier cotreated and untreated subjects, respectively. Represented as a ratio between the conditions, the in vitro pH-effect correlated linearly with clinical pH-effect based on the Cmax ratio and in a non-linear relationship based on AUC ratio. Additionally, several in silico approaches that use the in vitro dissolution data were found to be reasonably predictive of the clinical pH-effect. To explore the hypothesis that physicochemical properties are predictors of clinical pH-effect, statistical correlation analyses were conducted using linear sequential feature selection and partial least-squares regression. Physicochemical parameters did not show statistically significant linear correlations to clinical pH-effect for this data set, which highlights the complexity and poorly understood nature of the interplay between parameters. Finally, a strategy is proposed for implementation early in clinical development, to systematically assess the risk of clinical pH-effect for new molecular entities that integrates physicochemical analysis and in vitro, in vivo and in silico methods.

Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility.

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug-excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.

Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach.

Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing.

Understanding drug-excipient compatibility: oxidation of compound A in a solid dosage form.

Drug-excipient compatibility studies lay the foundation for designing a chemically stable formulation for clinical and commercial development. This article describes the investigation of oxidative degradation encountered with compound A (a phenylalanine-drug complex) in a capsule dosage form. Two wet- granulation capsule formulations (2.5-mg and 25-mg strengths) were developed using excipients that showed satisfactory stability from initial drug-excipient compatibility studies. Both capsule strengths were chemically stable at 50 degrees C (closed) for at least 18 weeks, but they showed discoloration. The 2.5-mg capsule exhibited degradation after four weeks at 40 degrees C/75%RH (open) besides discoloration. LC/MS analysis indicated that the degradants were oxidation products of the parent compound. Oxidation of compound A was investigated by forced degradation with peroxide, use of isotopically labeled water (H2(18)O) to study the source of oxygen, and use of different antioxidants to mitigate oxidation. Excipient(s) responsible for oxidation and discoloration were identified through extended and modified excipient compatibility studies. The discoloration was indicative of Maillard reaction occurring between a reducing sugar impurity from microcrystalline cellulose and L-phenylalanine in the drug complex. Reactive oxidative species generated by this reaction is postulated to cause oxidation of compound A.

Predicting effect of food on extent of drug absorption based on physicochemical properties.

PURPOSE: To develop a statistical model for predicting effect of food on the extent of absorption (area under the curve of time-plasma concentration profile, AUC) of drugs based on physicochemical properties. MATERIALS AND METHODS: Logistic regression was applied to establish the relationship between the effect of food (positive, negative or no effect) on AUC of 92 entries and physicochemical parameters, including clinical doses used in the food effect study, solubility (pH 7), dose number (dose/solubility at pH 7), calculated Log D (pH 7), polar surface area, total surface area, percent polar surface area, number of hydrogen bond donor, number of hydrogen bond acceptors, and maximum absorbable dose (MAD). RESULTS: For compounds with MAD >or= clinical dose, the food effect can be predicted from the dose number category and Log D category, while for compounds with MAD < clinical dose, the food effect can be predicted from the dose number category alone. With cross validation, 74 out of 92 entries (80%) were predicted into the correct category. The correct predictions were 97, 79 and 68% for compounds with positive, negative and no food effect, respectively. CONCLUSIONS: A logistic regression model based on dose, solubility, and permeability of compounds is developed to predict the food effect on AUC. Statistically, solubilization effect of food primarily accounted for the positive food effect on absorption while interference of food with absorption caused negative effect on absorption of compounds that are highly hydrophilic and probably with narrow window of absorption.

Use of 2,2'-azobis(2-amidinopropane) dihydrochloride as a reagent tool for evaluation of oxidative stability of drugs.

PURPOSE: To study the oxidative degradation of drugs using a hydrophilic free radical initiator, 2,2'-Azobis(-amidinopropane) dihydrochloride (AAPH). METHODS: AAPH was used as the free radical initiator to study oxidation of three model compounds (A, B, and C), which represent different oxidizable moieties. In the solution model, the drugs and AAPH were dissolved in a mixture of acetonitrile and aqueous buffer and incubated at elevated temperatures to evaluate oxidative degradation. The effects of pH and drug-AAPH ratio on the kinetics of the reaction were evaluated for compound A. Commonly used antioxidants were also evaluated by addition to solutions of drug and AAPH. In the solid-state model, blends of drug with microcrystalline cellulose were treated with AAPH and placed at elevated temperature and humidity to evaluate solid state oxidation. RESULTS: Use of AAPH resulted in selective oxidation of the model drugs by a free radical initiated process. The scope of the technique was further investigated in detail using compound A. The rate of oxidation of compound A varied directly with the concentration of AAPH. The pseudo first-order rate constants for the oxidative degradation were calculated from the kinetic data. The antioxidants were rank-ordered based on their quenching activity on the rates of AAPH initiated oxidation for compound A. The concept was extended to oxidation in solid state. CONCLUSIONS: The proposed AAPH model is useful in assessing oxidative stability of drug candidates in development.

Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility.

A novel multicompartment dissolution system was developed by modifying a conventional six-vessel United States Pharmacopoeia dissolution system to study the dissolution and possible precipitation of poorly soluble weak bases after oral administration. The modified system includes a "gastric" compartment, an "intestinal" compartment, an "absorption" compartment, and a reservoir to simulate the dissolution and absorption in the gastrointestinal tract. Dissolution profiles of 50-mg dipyridamole (pK(a) 6.0, 12.5) tablet (2 * 25 mg Persantine tablets), 25- and 50-mg cinnarizine (pK(a) 1.95, 7.5) powders, which are poorly soluble weak bases, were generated in the system using dissolution medium with different pHs in the "gastric" compartment. The in vitro dissolution results were compared with the in vivo oral exposure data in humans. For both dipyridamole and cinnarizine, the in vitro dissolution using the multicompartment system was able to predict the pH effect on oral exposure. The results from the multicompartment system are more closely correlated with the in vivo data, compared with that from the conventional dissolution test. The system showed that although both dipyridamole and cinnarizine completely dissolved in the gastric compartment at lower pH, approximately 36% (at 25-mg dose) and 40% (at 50-mg dose) of cinnarizine precipitated in the "intestinal" compartment whereas the precipitation of dipyridamole was <10% of the initial dose. The difference in the amount "absorbed" between these two compounds in vitro is therefore primarily attributed to the precipitation potential, although no in vivo data are available to confirm this result. The difference in the amount precipitated may be explained by the lower solubility and consequently higher degree of supersaturation of cinnarizine in the "intestinal" compartment.

Grouping solvents by statistical analysis of solvent property parameters: implication to polymorph screening.

The success rate of discovering new polymorphs by crystallization from solution may be increased if solvents with diverse properties are used during initial polymorph screening. In this study, eight solvent parameters, including hydrogen bond acceptor propensity, hydrogen bond donor propensity, polarity/dipolarity, dipole moment, dielectric constant, viscosity, surface tension and cohesive energy density (equal to square of solubility parameter), of 96 solvents were collected. Using the cluster statistical analysis of the parameters, these 96 solvents were separated into 15 solvent groups. Such solvent groups may provide guidelines for the judicious choice of solvents with diverse properties for polymorph screening.

Importance of using physiologically relevant volume of dissolution medium to correlate the oral exposure of formulations of BMS-480188 mesylate.

BMS-480188 is a weak base. The aqueous solubility of BMS-480188 is 0.036 mg/ml at pH 6.5 at 37 degrees C. The mesylate salt of BMS-480188 was prepared to improve its solubility. Capsules containing mesylate salt alone (Formulation A) or mesylate salt with excipients, including lactose, croscarmellose sodium, sodium lauryl sulfate, syloid and magnesium stearate (Formulation B), were prepared. Both formulations show similar dissolution profiles in 1l 0.01N HCl at 37 degrees C. However, the bioavailability of Formulations A and B is 5.7 and 24%, respectively, in monkeys. Since very small amount of fluid is available in the stomach of monkeys in fasted state, 30 ml of 0.01N HCl was used as the dissolution medium to simulate the ratio of the drug to dissolution medium in vivo. The dissolution studies in 30 ml of 0.01N HCl show that the amount of drug dissolved from the Formulation B is 80% greater than the Formulation A after 2h. These results are consistent with the higher bioavailability of the formulated capsules. The pK(a) of the free base is 3.0 and the apparent solubility of the mesylate salt (>20mg/ml) is much greater than the equilibrium solubility of BMS-480188 (1.08 mg/ml) in 0.01N HCl at 37 degrees C. Therefore, the mesylate salt of BMS-480188 converts to the free base in 0.01N HCl. The presence of excipients delays the conversion of the mesylate salt to the free base in the dissolution test using 30 ml medium, leading to a greater percentage of the dissolved drugs. This inhibitory effect of excipients is masked during the dissolution using 1l medium because the concentration of the dissolved drug is below the solubility limit of BMS-480188. This study demonstrates the importance of the volume of the dissolution medium for the in vitro dissolution test to qualitatively predict the bioavailability of a salt of weak base with low intrinsic aqueous solubility.