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The dissolution testing method described in the United States Pharmacopeia (USP) Chapter ⟨711⟩ is widely used for assessing the release of active pharmaceutical ingredients from solid dosage forms. However, extensive use over the years has revealed certain issues, including high experimental intervariability observed in specific formulations and the settling of particles in the dead zone of the vessel. To address these concerns and gain a comprehensive understanding of the hydrodynamic conditions within the USP 2 apparatus, computational fluid dynamic simulations have been employed in this study. The base design employed in this study is the 900 mL USP 2 vessel along with a paddle stirrer at a 50 rpm rotational speed. Additionally, alternative stirrer designs, including the hydrofoil, pitched blade, and Rushton impeller, are investigated. A comparison is also made between a flat-bottom tank and the USP round-bottom vessel of the same volume and diameter. Furthermore, this work examines the impact of various parameters, such as clearance distance (distance between the bottom of the impeller and bottom of the vessel), number of impeller blades, impeller diameter, and impeller attachment angle. The volume-average shear rate ( S tv ), fluid velocity ( U tv ), and energy dissipation rates (ϵ tv ) represent the key properties evaluated in this study. Comparing the USP2 design and systems with the same stirrer but flat-bottom vessel reveals more homogeneous mixing compared to the USP2 design. Analyzing fluid flow streamlines in different designs demonstrates that hydrofoil stirrers generate more suspension or upward movement of fluid compared to paddle stirrers. Therefore, when impellers are of a similar size, hydrofoil designs generate higher fluid velocities in the coning area. Furthermore, the angle of blade attachment to the hub influences the fluid velocity in the coning area in a way that the 60° angle design generates more suspension than the 45° angle design. The findings indicate that the paddle stirrer design leads to a heterogeneous shear rate and velocity distributions within the vessel compared with the other designs, suggesting suboptimal performance. These insights provide valuable guidance for the development of improved in vitro dissolution testing devices, emphasizing the importance of optimized design considerations to minimize hydrodynamic variability, enhance dissolution characterization, and reduce variability in dissolution test results. Ultimately, such advancements hold potential for improving in vitro-in vivo correlations in drug development.

Background: Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds., Methods: The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate)., Results: The results showed that there is a solubility vs. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models., Conclusions: The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H 2 CO 3 -CO 2 interconversion kinetics to achieve good predictions of intestinal drug dissolution., (© 2024. The Author(s).)

BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.

This study investigated the combined effect of pH and surfactant on the solubility and dissolution of ketoprofen (KP), a highly permeable and an ionizable and water-poorly soluble drug in gastrointestinal tract. The equilibrium solubility of KP was determined in buffers at the pH range from 4.0 to 6.8 and sodium lauryl sulfate (SLS) concentrations from 0% to 2.0%. Its intrinsic dissolution rate was measured in the same media using a rotating disk apparatus. A simple additive model accounting for the free unionized KP and ionized KP(-) forms, and their corresponding micellar forms was employed to study the in vitro solubility and dissolution behavior. Non-linear regression analysis showed that the proposed model agreed well with the experimental data, with R(sq)=0.96 (P<0.0001) for the solubility study, and R(sq)=0.98 (P<0.0001) for the intrinsic dissolution rate measurement. The pK(a) and c(KP) values are estimated as 4.76+/-0.00 and 0.253+/-0.05 mg/mL, respectively, in good agreement with literature reports. The micellar solubilization coefficient k(*) for the unionized [KP](micelle) is 757+/-165 L/mol, whereas the value k(**) for the ionized [KP(-)](micelle) is 9.88+/-6.70 L/mol. The diffusion coefficients of various species: KP, KP(-), [KP](micelle), and [KP(-)](micelle), are 7.68 x 10(-6), 1.54 x 10(-6), 2.32 x 10(-7), and 2.13 x 10(-20)cm(2)/s, respectively. The maximum enhancement of solubilization is approximately 232-fold, while the maximum dissolution amplification is only 54-fold because of the smaller diffusivity of micellar species. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of KP along the gastrointestinal tract, when the pH increases from 1-2 in the stomach to 5-6 in the duodenum. The results suggest that the KP dissolves very rapidly in small intestine, implying that its absorption will be predominantly controlled by gastric emptying, and only minimally limited by the subsequent dissolution processes. This behavior is very similar to BCS I drugs, thus KP may be considered for possible waivers of bioequivalence.

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development. [ABSTRACT FROM AUTHOR]

The solubility of fenofibrate in pH 6.8 McIlvaine buffers containing varying concentrations of sodium lauryl sulfate was determined. The dissolution behavior of fenofibrate was also examined in the same solutions with rotating disk experiments. It was observed that the enhancement in intrinsic dissolution rate was approximately 500-fold and the enhancement in solubility was approximately 2000-fold in a pH 6.8 buffer containing 2% (w/v) sodium lauryl sulfate compared to that in buffer alone. The micellar solubilization equilibrium coefficient (k*) was estimated from the solubility data and found to be 30884 ±213 L/mol. The diffusivity for the free solute, 7.15 × 10-6 cm²/s, was calculated using Schroeder's additive molal volume estimates and Hayduk-Laurie correlation. The diffusivity of the drug-loaded micelle, estimated from the experimental solubility and dissolution data and the calculated value for free solute diffusivity, was 0.86 × 10-6 cm²/s. Thus, the much lower enhancement in dissolution of fenofibrate compared to its enhancement in solubility in surfactant solutions appears to be consistent with the contribution to the total transport due to enhanced micellar solubilization as well as a large decrease (∼8-fold) in the diffusivity of the drug-loaded micelle. [ABSTRACT FROM AUTHOR]

The purpose of this report was to investigate the feasibility of using disk intrinsic dissolution rate (DIDR) to determine solubility class membership. We employed a VanKel dissolution apparatus fitted with a Wood’s intrinsic dissolution die. To test the robustness of the method, variations of DIDR with compression force, dissolution volume, distance of the drug disk from the bottom of the dissolution vessel, and drug disk rotation speed were studied using furosemide and metoprolol in pH 4.5 acetate buffer as a model system. The DIDRs of six low solubility and nine high solubility model drugs were then determined at pH 1.2, 4.5, and 6.8 and compared to their BCS solubility class membership. It was found that the compression force, dissolution medium volume, and die position had no significant effect on DIDR for the system studied. The proposed compression force, dissolution volume, die position, and rotation speed are 2000 psi, 900 ml, 0.5 in., and 100 rpm, respectively. The test results obtained from 15 model BCS drugs show a good relationship between the DIDR and BCS solubility classification with 0.1 mg/min/cm2 as a class boundary unless the dose is either extremely low or high where discrepancies may exist between the solubility and DIDR methods. Therefore, more scientific research and debates are needed before considered for regulatory purpose. [Copyright &y& Elsevier]

Age-appropriate pediatric formulations for oral administration can be challenging to formulate. Development of such formulations is often time consuming, labor-intensive and costly. The Biopharmaceutical Classification System (BCS), developed more than two decades ago, is used to develop suitable oral drug formulations for adult use. In theory, some of the same principles could be applied to formulate pediatric oral liquid dosage forms. However, the present BCS system was developed using adult gastrointestinal physiologic factors. Direct extrapolation of this method to develop pediatric oral dosage forms is inappropriate due to differences in adult and pediatric gastrointestinal physiologic differences during development. To date age-appropriate BCS to guide pediatric oral liquid formulation development has not been developed for various pediatric subpopulations. The objective of this study was to provisionally classify oral liquid formulations of extemporaneously prepared drugs at our institution into an age-appropriate BCS class after elimination of any duplicate listing when matched with the most current World Health Organization's Essential Medicines List for Children available at the time of this study and other published studies that may have reported BCS classification of drugs used as extemporaneous oral liquid formulations in children to treat chronic or rare diseases. A total of 96 orally administered extemporaneously compounded liquid formulations were included in this classification. Dose numbers were calculated using age-appropriate initial gastric volume for neonates, 6-month-old infants, and children up to 6 years of age. Using age-appropriate initial gastric volumes and pediatric and neonatal Lexicomp® age-specific maximal dosing recommendations for calculation of dose numbers, the solubility classes shifted for 62.5% of the drugs studied. A significant number of currently used extemporaneously compounded oral liquid formulations for age groups of children included in this study may not provide formulations with predictable safety and efficacy. Factors used in development of adult BCS cannot be applied directly to pediatric subpopulations. BCS class change following application of principals of GI ontogeny and physiology to commonly used APIs used off-label in extemporaneous oral liquid formulations in pediatric patients with chronic diseases. BCS-Biopharmaceutical Classification System, pBCS-Pediatric Biopharmaceutical Classification System Image, graphical abstract [ABSTRACT FROM AUTHOR]

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the 'highly soluble' criteria according to World Health Organization ( WHO), the European Medicines Agency ( EMA), and the United States Food and Drug Administration ( US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2 D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence ( BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci [ABSTRACT FROM AUTHOR]