A commentary on "Are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?"

The clearance concept has been used in pharmacokinetics for over 50 years. However, there is still much debate regarding mathematical clearance models. A recent article discussed that there is a critical error in a basic assumption that leads to the mechanistic hepatic clearance models (Benet, L.Z., Sodhi, J.K., 2024. Are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance? European Journal of Pharmaceutical Sciences 196, 106,753. https://doi.org/10.1016/j.ejps.2024.106753). This commentary discusses this point based on the extended clearance model (ECM), which is increasingly used in modern drug discovery and development. Confusion about clearance can be avoided by using clearly defined drug concentrations based on hierarchical body structures.

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer.

The purpose of the present study was to clarify whether the precipitation profile of a drug in bicarbonate buffer (BCB) may differ from that in phosphate buffer (PPB) by a well-controlled comparative study. The precipitation profiles of structurally diverse poorly soluble drugs in BCB and PPB were evaluated by a pH-shift precipitation test or a solvent-shift precipitation test (seven weak acid drugs (pKa: 4.2 to 7.5), six weak base drugs (pKa: 4.8 to 8.4), one unionizable drug, and one zwitterionic drug). To focus on crystal precipitation processes, each ionizable drug was first completely dissolved in an HCl (pH 3.0) or NaOH (pH 11.0) aqueous solution (450 mL, 50 rpm, 37 °C). A 10-fold concentrated buffer solution (50 mL) was then added to shift the pH value to 6.5 to initiate precipitation (final volume: 500 mL, buffer capacity (ß): 4.4 mM/ΔpH (BCB: 10 mM or PPB: 8 mM), ionic strength (I): 0.14 M (adjusted by NaCl)). The pH, ß, and I values were set to be relevant to the physiology of the small intestine. For an unionizable drug, a solvent-shift method was used (1/100 dilution). To maintain the pH value of BCB, a floating lid was used to avoid the loss of CO2. The floating lid was applied also to PPB to precisely align the experimental conditions between BCB and PPB. The solid form of the precipitants was identified by powder X-ray diffraction and differential scanning microscopy. The precipitation of weak acids (pKa ≤ 5.1) and weak bases (pKa ≥ 7.3) was found to be slower in BCB than in PPB. In contrast, the precipitation profiles in BCB and PPB were similar for less ionizable or nonionizable drugs at pH 6.5. The final pH values of the bulk phase were pH 6.5 ± 0.1 after the precipitation tests in all cases. All precipitates were in their respective free forms. The precipitation of ionizable weak acids and bases was slower in BCB than in PPB. The surface pH of precipitating particles may have differed between BCB and PPB due to the slow hydration process of CO2 specific to BCB. Since BCB is a physiological buffer in the small intestine, it should be considered as an option for precipitation studies of ionizable weak acids and bases.

Dissolution Profiles of Immediate Release Products of Various Drugs in Biorelevant Bicarbonate Buffer: Comparison with Compendial Phosphate Buffer.

PURPOSE: The purpose of this study was to clarify the extent to which the dissolution profiles of immediate release (IR) products of various drugs differ between biorelevant bicarbonate buffer (BCB) and compendial phosphate buffer (PPB). METHODS: The dissolution profiles of the IR products of fifteen poorly soluble ionizable drugs were measured in BCB and PPB. BCB was set to be relevant to the small intestine (pH 6.8, 10 mM). The pH was maintained using the floating lid method. The Japanese pharmacopeia second fluid (JP2, 25 mM phosphate buffer, nominal pH 6.8) was used as compendial PPB. The compendial paddle apparatus was used for the dissolution tests (500 mL, 50 rpm, 37°C). RESULTS: In 11/15 cases, a difference in dissolved% (< 0.8 or > 1.25-fold) was observed at a time point. In 4/15 cases, the ratio of the area under the dissolution curve was not equivalent (< 0.8 or > 1.25-fold). In the cases of free-form drugs, the dissolution rate tended to be slower in BCB than in JP2. In the case of salt-form drugs, a marked difference was observed for the cases that showed supersaturation. However, no trend was observed in the differences. CONCLUSIONS: Many IR products showed differences in the dissolution profiles between biorelevant BCB and compendial PPB. With the floating lid method, BCB is as simple and easy to use as PPB. Biorelevant BCB is recommended for dissolution testing.

Dissolution Profiles of Oral Disintegrating Tablet with Taste Masking Granule Polymer Coating in Biorelevant Bicarbonate Buffer.

The current study aimed to explore the impact of buffer species on the dissolution behavior of orally disintegrating tablets (ODT) containing a basic polymer and its influence on bioequivalence (BE) prediction. Fexofenadine hydrochloride ODT formulations were used as the model formulations, Allegra® as the reference formulation, and generic formulations A and B as the test formulations. Allegra®, generic A, and generic B are ODT formulations that contain aminoalkyl methacrylate copolymers E (Eudragit® E, EUD-E), a basic polymer commonly used to mask the bitter taste of drugs. Both generic A and generic B have been known to be bioequivalent to Allegra®. The dissolution tests were conducted using a compendial paddle, with either bicarbonate (10 mM, pH 6.8) or phosphate buffer (25 mM, pH 6.8) as the dissolution media. A floating lid was employed to cover the surface of the bicarbonate buffer to prevent volatilization. Results indicated that in phosphate buffer, the dissolution profiles of Allegra and generic B significantly varied from that of generic A, whereas in the bicarbonate buffer, the dissolution profiles of Allegra, generic A, and generic B were comparable. These findings suggest that the use of bicarbonate buffer may offer a more precise prediction of human bioequivalence compared to phosphate buffer.

Bicarbonate buffer dissolution test with gentle mechanistic stress for bioequivalence prediction of enteric-coated pellet formulations.

This study aimed to develop a dissolution test that can predict the bioequivalence (BE) of enteric-coated pellet formulations. The original duloxetine hydrochloride capsule (reference formulation (RF); Cymbalta® 30 mg capsule) and four generic test formulations (two capsules (CP) and two orally disintegrating tablets (OD)) were used as model formulations. Clinical BE studies were conducted on 24-47 healthy male subjects under fasting conditions. Dissolution tests were performed using a compendial paddle method (PD) (paddle speed: 50 rpm) and a flow-through cell method (FTC) (flow rate: 4 mL/min). For a further test, cotton balls were added to the vessel to apply gentle mechanistic stress to the formulations, and paddle speed was reduced to 10 rpm (paddle with cotton ball method (PDCB)).All the dissolution tests were conducted with 0.01 M HCl (pH 2.0) for 0.5 h followed by 10 mM bicarbonate buffer solutions (pH 6.5) for 4 h. One each of the two CP and two OD showed BE with RF. PDCB was able to discriminate between BE and non-BE formulations, while this was not possible with PD and FTC. In PDCB, the cotton balls intermittently moved the pellets near the vessel bottom. PDCB is useful for predicting BE during formulation development.

Effect of Food Viscosity on Drug Dissolution.

PURPOSE: The purpose of the present study was to investigate the effect of food viscosity on the dissolution rate of a drug. There are two types of viscosity, macroviscosity and microviscosity. Macroviscosity affects the diffusion layer thickness, whereas microviscosity affects the molecular diffusion coefficient. The mass transfer coefficient (kc) in the intrinsic dissolution rate (IDR) depends on the viscosity (η) as kc ∝ ηa (a is an exponent on η). In theory, for rotating flow over a disk, if a thickener increases only macroviscosity, a = -1/6, and if it increases both macroviscosity and microviscosity equally, a = -7/6. METHOD: Benzocaine was used as a model drug. Hydroxypropyl cellulose (HPC) and methylcellulose (MC) were employed as control thickeners that increase only macroviscosity. Sucrose was employed as a control thickener for both macroviscosity and microviscosity. The FDA breakfast homogenate (BFH) was diluted with distilled water or 1 mM HCl with/without pepsin digestion. The IDR value was measured by the paddle-over-disk method. RESULTS: The η value of 30% BFH distilled water was 209 mPa∙s, about 300 times higher than distilled water. It was further increased by HCl (430 mPa∙s), and reduced by pepsin digestion (35 mPa∙s). The kc value was little affected by BFH (a = 0.00 to -0.09), slightly less than those in HPC (a = -0.19) and MC (a = -0.21). Sucrose decreased the kc value more significantly (a = -0.70). CONCLUSION: The IDR and kc values of benzocaine were little affected by BFH, suggesting that BFH increased only macroviscosity.

Food and bile micelle binding of quaternary ammonium compounds.

Background and Purpose: Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC). However, the mechanism has remained unclear. The purpose of the present study was to investigate the bile micelle and food binding of QACs as a mechanism of the negative food effect. Experimental Approach: Trospium (TRS), propantheline (PPT), and ambenonium (AMB) were selected as model QAC drugs. The oral absorption of these QACs has been reported to be reduced by 77% (TRS), > 66% (PPT), and 79% (AMB), when taken with food. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) were used as the simulated intestinal fluid. The unbound fraction (fu) of the QACs in these media was measured by dynamic dialysis. Key Results: The fu ratios (FeSSIF/ FaSSIF) were 0.67 (TRS), 0.47 (PPT), and 0.76 (AMB). When BFH was added to FeSSIF, it was reduced to 0.39 (TRS), 0.28 (PPT), and 0.59 (AMB). Conclusion: These results suggested that bile micelle and food binding play an important role in the negative food effect on the oral absorption of QACs.

Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing.

The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.8, 50 mM phosphate). The solid form of the residual particles was identified by Raman spectroscopy. In the pH range below 6.5, the equilibrium solubility in phosphate buffer was lower than that in the unbuffered solutions (pH adjusted by HCl and NaOH). Raman spectra showed that the residual solid was a phosphate salt of PRZ. In the pH range above 6.5, the pH-solubility profiles in the phosphate buffer solutions and the unbuffered solutions were the same. The residual solid was a PRZ freebase (PRZ-FB). In the dissolution test, PRZ-HCl particles first changed to a phosphate salt within 5 min, then gradually changed to PRZ-FB after several hours. Since the intestinal fluid is buffered by the bicarbonate system in vivo, the dissolution behavior in vivo may not be properly evaluated using a phosphate buffer solution. For drugs with a low phosphate solubility product, it is necessary to consider this aspect.

Prediction of Liquid-Liquid Phase Separation at the Dissolving Drug Salt Particle Surface.

During the dissolution of drug salt particles, liquid-liquid phase separation (LLPS) of a free form can occur within the unstirred water layer (UWL) of the particles (UWL-LLPS). Theoretically, UWL-LLPS occurs when the free form concentration at the salt particle surface (C0) exceeds the intrinsic LLPS concentration (S0LLPS) of the free form. In the present study, we attempted to predict UWL-LLPS based on the intrinsic physicochemical properties of drugs. Cyproheptadine hydrochloride (CPH-HCl), diclofenac sodium (DCF-Na), papaverine hydrochloride (PAP-HCl), and propafenone hydrochloride (PRF-HCl) were selected as model drug salts. The pH0 and C0 values at pHs 4.0-9.5 (citric acid, phosphoric acid, and boric acid, buffer capacity = ca. 4 mM/ΔpH) were calculated using the pKa, solubility product (Ksp), and diffusion coefficient (D) of a drug. S0LLPS was measured using the pH-shift method. UWL-LLPS was predicted to occur when C0 ≥ S0LLPS. The prediction result was then compared with UWL-LLPS observed at each pH by polarized light microscopy (PLM). The pH-LLPS concentration (SpHLLPS) profile of each drug was also measured. UWL-LLPS was approximately correctly predicted for CPH-HCl, DCF-Na, and PRF-HCl. However, UWL-LLPS was not observable when C0 was close to S0LLPS. Furthermore, UWL-LLPS was not accurately predicted in the case of PAP-HCl. The pH-SpHLLPS profile of PAP did not follow the Henderson-Hasselbalch equation, probably because of the formation of cationic aggregates. In conclusion, UWL-LLPS was approximately predictable for drug salts using their intrinsic physicochemical properties (Ksp, pKa, D, and S0LLPS), except for PAP-HCl.

Dissolution Profiles of Poorly Soluble Drug Salts in Bicarbonate Buffer.

PURPOSE: The purpose of the present study was to investigate the effect of buffer species on the dissolution profiles of poorly soluble drug salts, focusing on bicarbonate buffer (BCB). METHODS: Pioglitazone HCl (PIO HCl) and dantrolene sodium (DNT Na) were used as model drugs. Non-sink dissolution tests were performed using phosphate buffer (PB) and BCB (pH 6.5, buffer capacity: 4.4 mM/pH, ionic strength: 0.14 M, with/ without bile micelles). The pH value of BCB was maintained using a floating lid that avoided the loss of CO2. The particles collected at the early stage of dissolution (< 5 min) were analyzed by powder X-ray diffraction, polarized light microscopy, and scanning electron microscopy. A bulk-phase pH shift precipitation test was also performed. RESULTS: The dissolution of PIO HCl was slower in BCB than in PB, whereas that of DNT Na was faster in BCB than in PB. The same trend was observed in the presence of bile micelles. Free-form precipitation on the surface of salt particles was observed early in their dissolution in both BCB and PB. However, the surface textures in BCB and PB were different. The bulk-phase precipitation of PIO was little affected by buffer species, whereas that of DNT was affected, but oppositely to the dissolution profile. CONCLUSION: The dissolution profiles of PIO HCl and DNT Na in BCB were markedly different from those in PB. Free-form precipitation on the particle surface, rather than in the bulk phase, was affected by buffer species in the dissolution test.

Application of Population Balance Model to Simulate Precipitation of Weak Base and Zwitterionic Drugs in Gastrointestinal pH Environment.

The purpose of the present study was to evaluate whether the population balance model (PBM) could be a suitable model for the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment. Five poorly soluble drugs were used as model drugs (dipyridamole, haloperidol, papaverine, phenazopyridine, and tosufloxacin). PBM consists of the equations for primary nucleation, secondary nucleation, and particle growth. Each equation has two empirical parameters. The pH shift (pH-dumping) precipitation test (pH 3.0 to 6.5) was used to determine the model parameters for each drug. It was difficult to determine all six parameters by simultaneously fitting them to the precipitation profiles. Therefore, the number of model parameters was reduced from six to three by neglecting the secondary nucleation process and applying a common exponent number for the particle growth equation. Despite reducing the parameter number, PBM appropriately described the precipitation profiles in the pH shift tests. The constructed PBM model was then used to predict the precipitation profiles in an artificial stomach-intestine transfer (ASIT) test. PBM appropriately predicted the precipitation profiles in the ASIT test. These results suggested that PBM can be a suitable model to represent the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment for biopharmaceutics modeling and simulation.

Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs.

The purpose of the present study was to provide the experimental and theoretical basis of bioequivalence (BE) dissolution test criteria for formulation development of high solubility-low permeability drugs. According to the biowaiver scheme based on the biopharmaceutics classification system (BCS), for BCS class III drugs, a test formulation and a reference formulation are predicted to be BE when 85% of the drug dissolves within 15 min (T85% < 15 min) in the compendial dissolution test. However, previous theoretical simulation studies have suggested that this criterion may possibly be relaxed for use in practical formulation development. In the present study, the dissolution profiles of 14 famotidine formulations for which BE has been clinically confirmed were evaluated by the compendial dissolution test at pH 1.2 and 6.8. The plasma concentration-time profiles of famotidine formulations were simulated using the dissolution data. In addition, virtual simulations were performed to estimate the range of dissolution rates to be bioequivalent. The fastest and slowest dissolution rates among the famotidine formulations were T85% = 10 min and T85% = 60 min at pH 6.8, respectively. The virtual simulation BE study suggested that famotidine formulations can be bioequivalent when T85% < 99 min. In the case of BCS III drugs, the rate-limiting step of oral drug absorption is the membrane permeation process rather than the dissolution process. Therefore, a difference in the dissolution process has less effect on BE. These results contribute to a better understanding of the biowaiver approach and would be of great help in the formulation development of BCS class III drugs.

Prediction of Oral Drug Absorption in Rats from In Vitro Data.

PURPOSE: In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats. The purpose of the present study was to evaluate the predictability of the GUT framework for rat Fa. METHOD: The Fa values of 20 model drugs (a total of 39 Fa data) were predicted in a bottom-up manner. Based on the literature survey, the bile acid concentration (Cbile) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pKa, molecular weight, intrinsic solubility, bile micelle partition coefficients, and Caco-2 permeability were used as input data. RESULTS: The Fa values were appropriately predicted for highly soluble drugs (absolute average fold error (AAFE) = 1.65, 18 Fa data) and poorly soluble drugs (AAFE = 1.57, 21 Fa data). When the species difference in Cbile was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High Cbile in rats reduces the free fraction of drug molecules available for epithelial membrane permeation while increasing the solubility of poorly soluble drugs. CONCLUSION: The Fa values in rats were appropriately predicted by the GUT framework. This result would be of great help for a better understanding of species differences and model-informed preclinical formulation development.

Dissolution Profiles of Carbamazepine Cocrystals with Cis-Trans Isomeric Coformers.

PURPOSE: The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers. METHOD: CBZ cocrystals with maleic acid (MLE) and fumaric acid (FUM) (CBZ-FUM anhydrate (CBZ-FUM AH) and monohydrate (CBZ-FUM H2O)) were employed as model cocrystals. Hydroxypropyl　methylcellulose (HPMC), polyvinylpyrrolidone, and polyethylene glycol 6000 (PEG) were used as precipitation inhibitors. Dissolution tests were performed under a non-sink condition. Residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscope, and scanning electron microscope. RESULTS: All cocrystals showed little supersaturation in the absence of a polymer. In 0.1% HPMC, CBZ-FUM AH showed significant supersaturation, whereas CBZ-MLE and CBZ-FUM H2O did not for the first two hours. HPMC reduced the initial dissolution rate of CBZ-MLE and CBZ-FUM H2O while inducing the highest supersaturation among the polymers after 96 h. The particle surface changed from a smooth plane to a striped pattern, but little or no CBZ DH was detected. CONCLUSION: The cocrystals with cis-trans isomeric coformers showed different dissolution profiles. HPMC increased the dissolution rate of CBZ-FUM AH by inhibiting PS-SMPT but reduced the dissolution rate of CBZ-MLE and CBZ-FUM H2O without inducing PS-SMPT. The striped pattern was suggested to be due to surface etching rather than PS-SMPT.

Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets.

The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bicarbonate buffer solution (pH 5.5-7.5; 5-50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4-8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ∆pH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.

Effect of divalent and trivalent metal ions on artificial membrane permeation of fluoroquinolones.

The purpose of the present study was to evaluate the predictability of PAMPA for the effect of metal ions on the bioavailability of fluoroquinolones (FQ). Eleven FQs and seven metal ions were employed in this study. The PAMPA membrane consisted of a 10 % soybean lecithin (SL) - decane solution. A drug solution in MES buffer with or without a metal ion (added as a chloride salt) was added to the donor compartment. In the absence of metal ions, FQ showed relatively high permeability (> 5 × 10-6 cm/sec) in SL-PAMPA despite their hydrophilic and zwitterionic properties. As the PAMPA permeability ratio with/without metal ions became smaller, the urinary excretion and AUC ratios tended to be smaller, suggesting that SL-PAMPA is a suitable in vitro model to evaluate the potential effect of metal ions on the bioavailability of FQ. However, the reduction in AUC and urinary excretion was overestimated for low solubility metal ion formulations (dried aluminum hydroxide gel and La2(CO3)3・8H2O). In such cases, the dissolution of the metal ion formulations and the permeation of FQs should be simultaneously evaluated.

Thermodynamic Correlation between Liquid-Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules.

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid−liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS−0.0095Tm−310 for 310 K). The S0LLPS values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed log10S0C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit).

A Critical Overview of the Biological Effects of Excipients (Part II): Scientific Considerations and Tools for Oral Product Development.

It is now recognized that a number of excipients previously considered to be "inert" have the capacity to alter drug oral bioavailability through a range of in vivo effects. The various mechanisms through which an excipient can affect in vivo gastrointestinal physiology and drug absorption characteristics were explored in "A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption." The next critical issue that needs to be discussed is how these biological effects are evaluated. Therefore, in Part 2 of this critical overview, the in vitro, in vivo, and in silico methods for evaluating excipient effects are considered. Examples are provided to illustrate how such studies employing these various procedures have been used to promote formulation understanding and optimization. Finally, a discussion of how the Center for Drug Evaluation and Research applies these tools to support biowaivers is provided.

Salt Solubility and Disproportionation - Uses and Limitations of Equations for pHmax and the In-silico Prediction of pHmax.

A multiphasic mass action equilibrium model was used to study the phase properties near the critical pH ('pHmax') in an acid-base transformation of a solid drug salt into its corresponding solid free base form in pure water slurries. The goal of this study was to better define the characteristics of disproportionation of pharmaceutical salts, objectively (i) to classify salts as µ-type (microclimate stable) or δ-type (disproportionation prone) based on the relationship between the calculated pHmax and the calculated pH of the saturated salt solution, (ii) to compare the distribution of µ/δ-type salts to predictions from the disproportionation potential equation introduced by Merritt et al.,20 (iii) to determine if the intrinsic solubility of the free base, S0, can be predicted from the measured µ-type salt solubility as a means of estimating the value of pHmax, (iv) to determine S0 directly from the measured δ-type salt solubility, and (v) to address some of the limitations of the equations commonly used to calculate pHmax. When the salt solubility is measured for a basic API (pKa of which is known), but the experimental value of S0 is unavailable, a potentially useful simple screen for disproportionation is still possible, since pHmax can be estimated from a 'µ-predicted' (objective iii) or 'δ-measured' S0 (objective iv). Twelve model weak base API were selected in the study. For each API, 2-17 different salt forms with reported salt solubilities in distilled water were sourced from the literature. In all, 73 salt solubility values based on 29 different salt-forming acids comprise the studied set. All the corresponding free base solubility values were available. The pKa values for all the acids and bases studied are generally well known. For each API salt, an acid-base titration simulation was performed, anchored to the measured salt solubility value, using the general mass action analysis program pDISOL-X. The log S-pH profiles were drawn out by analytic continuity from pH 0 to 13, as described in detail previously.24 Potentially useful in-silico models were developed that correlate pS0 to linear functions of the salt solubility in water, pSw, the partition coefficient of the salt-forming acid (log POCTacid) and the melting point (mp) of the drug salt, thereby enabling the derivation of the approximate pHmax value from the predicted pS0.

Is equilibrium slurry pH a good surrogate for solid surface pH during drug dissolution?

The purpose of the present study was to investigate the suitability of equilibrium slurry pH (pHeq) as a surrogate of solid surface pH during drug dissolution (pH0). A comprehensive calculation scheme for pHeq and pH0 was formalized based on the principle of charge neutrality (equilibrium charge neutrality for pHeq and charge flux neutrality for pH0). The formalized scheme was then used to investigate the validity of pH0 ≈ pHeq approximation. The approximation of pH0 ≈ pHeq was suggested to be accurate for small molecules (ca. MW = 150) in high concentration buffer media (ca. buffer capacity = 30 mM/ΔpH). In addition, it is valid provided no precipitation of its free form for salts (vice versa for free forms) in both the slurry pH measurement and at the dissolving drug surface. The formalized calculation scheme is simple and applicable to free and salt form drugs in unbuffered and buffered media including bicarbonate buffer. The computational expense is very small so that it is applicable to various computer simulations such as biopharmaceutics modeling and simulation.