Use of physiologically-based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine.

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.

Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

The Effect of Sampling Cannula on In Vitro Dissolution Testing with USP Paddle Method.

In vitro dissolution tests are widely used as quality control tools for drug products in development and manufacturing. Dissolution acceptance criteria are one of the important factors assessed during the regulatory review process. Understanding potential sources of variability is critical and a key to assuring reliable results are obtained when using a standardized system for in vitro dissolution testing. Sampling cannulas are commonly used to withdraw sample aliquots from dissolution medium and are potentially one of the testing factors that can contribute to variabilities in dissolution testing. However, there are still no clear requirements on the size or setting (intermittent or stationary) of sampling cannulas for dissolution testing. Thus, the objective of this study is to evaluate whether various sizes and sampling cannula settings yield different dissolution results using the USP 2 apparatus. Sampling cannulas with outer diameter (OD) ranging from 1.6 mm to 9.0 mm were used in dissolution testing with either intermittent or stationary setting to collect sample aliquots at multiple time points. The dissolution results at each time point were statistically analyzed for effects of both OD and setting of sampling cannula on drug release from 10 mg prednisone disintegrating tablets. Dissolution results indicated both size and setting of the sampling cannula may cause significant systematic errors, even though the dissolution apparatus has been calibrated. The degree of interference in dissolution results was directly related to the OD of the sampling cannula. Size of sampling cannula and setting of sampling procedure should be documented in standard operating procedures (SOP)  for dissolution testing during method development.

A top-down spectroscopic approach for correlating coating thickness distributions with the dissolution profiles of enterically coated pellets.

Pharmaceutical dosage forms such as tablets and capsules are often coated with a functional polymer to modify the drug release. To obtain the drug release profiles, ensure quality control and predict in-vivo performance, dissolution studies are performed. However, dissolution tests are time-consuming, sample destructive and do not readily allow for at-line or in-line characterization. Rapid assessment of functional coatings is essential for products where a single capsule is comprised of hundreds of functionally-coated pellets and the collective drug release kinetics of the entire capsule depends on contributions from each pellet. Here, single Raman measurements were used to evaluate the coating thickness distributions of a dosage form comprised of small, functionally-coated pellets in capsules. First, the composition and physicochemical properties of pellets were characterized by multivariate analysis assisted Raman mapping of pellet cross-sections. Second, a method of collecting single Raman spectrum with spectral contributions from the coating and API layers was developed and optimized to estimate the thickness of coatings. The coating thicknesses obtained from single Raman measurements of pellets in each capsule revealed thickness distributions that correlated with the dissolution profiles (capsules with one distribution had single stage release and capsules with two distributions had a two-stage release). Finally, an unsupervised multivariate analysis method was demonstrated as a rapid and efficient way to correlate dissolution profiles of enterically coated pellets. In summary, this study presents a non-destructive and rapid characterization method for assessing coating thickness and has the potential to be applied in process analytical technologies to ensure coating uniformity and predict product dissolution rate performance.

Development of In Vitro Dissolution Testing Methods to Simulate Fed Conditions for Immediate Release Solid Oral Dosage Forms.

In vitro dissolution testing is widely used to mimic and predict in vivo performance of oral drug products in the gastrointestinal (GI) tract. This literature review assesses the current in vitro dissolution methodologies being employed to simulate and predict in vivo drug dissolution under fasted and fed conditions, with emphasis on immediate release (IR) solid oral dosage forms. Notable human GI physiological conditions under fasted and fed states have been reviewed and summarized. Literature results showed that dissolution media, mechanical forces, and transit times are key dissolution test parameters for simulating specific postprandial conditions. A number of biorelevant systems, including the fed stomach model (FSM), GastroDuo device, dynamic gastric model (DGM), simulated gastrointestinal tract models (TIM), and the human gastric simulator (HGS), have been developed to mimic the postprandial state of the stomach. While these models have assisted in expanding physiological relevance of in vitro dissolution tests, in general, these models lack the ability to fully replicate physiological conditions/processes. Furthermore, the translatability of in vitro data to an in vivo system remains challenging. Additionally, physiologically based pharmacokinetic (PBPK) modeling has been employed to evaluate the effect of food on drug bioavailability and bioequivalence. Here, we assess the current status of in vitro dissolution methodologies and absorption PBPK modeling approaches to identify knowledge gaps and facilitate further development of in vitro dissolution methods that factor in fasted and fed states. Prediction of in vivo drug performance under fasted and fed conditions via in vitro dissolution testing and modeling may potentially help efforts in harmonizing global regulatory recommendations regarding in vivo fasted and fed bioequivalence studies for solid oral IR products.

An In Vitro Dissolution Method for Testing Extended-Release Tablets Under Mechanical Compression and Sample Friction.

The release and dissolution of an active pharmaceutical ingredient (API) from the solid oral formulation into the gastrointestinal (GI) tract is critical for the drug's absorption into systemic circulation. Extended-release (ER) solid oral dosage forms are normally subjected to physical shear and grinding forces as well as pressure exerted by peristaltic movements when passing through the GI tract. The complex physical contraction and sample friction exerted by the GI tract are not simulated well by compendial dissolution methods. These limitations render traditional in vitro dissolution testing unable to discriminate and predict a product's in vivo performance. The objective of this study was to develop a dissolution method that better simulates the GI environment that products are subject to when taken by patients. A newly designed Mechanical Apparatus under GI Conditions (MAGIC) was assembled with a dissolution platform and mechanical capabilities to allow in vitro dissolution testing under sample contractions and friction. The dissolution platform, with medium flow-through configuration, was manufactured by 3D printing. A 60 mg polymer matrix-based ER nifedipine product was tested. To simulate GI physiological conditions during the dissolution testing, the flow rate of the medium, and a combination of mechanical compression with rotation induced sample friction at various rotation frequencies were explored. The polymer matrix-based nifedipine ER formulation used here failed its controlled release functionality in the simulated GI environment under mechanical compression and sample friction. The results showed that the MAGIC system, with flow-through configuration under compression and sample friction, has advantages over compendial methods in testing ER solid oral formulations.

In Vitro Analysis of N-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions.

Importance: A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. Objective: To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. Design, Setting, and Participants: One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 µmol/L) to higher concentrations (10 000 µmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. Main Outcomes and Measures: NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. Results: At a supraphysiologic nitrite concentration (ie, 10 000 µmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 µmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 µmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 µmol/L) or 10-fold physiologic (1000 µmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 µmol/L). Conclusions and Relevance: In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 µmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.

Development and Validation of Sample Preparation and an HPLC Analytical Method for Dissolution Testing in Fed-State Simulated Gastric Fluid-Illustrating Its Application for Ibuprofen and Ketoconazole Immediate Release Tablets.

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.

Nifedipine Release From Extended-Release Solid Oral Formulations Using In Vitro Dissolution Testing Under Simulated Gastrointestinal Compression.

Drug release plays a critical role in defining bioavailability for an extended release solid oral drug products and predictive dissolution tests are desired to establish clinically relevant quality standards for batch release. The objective of this study focuses on exploring the possible impacts of 1 gastrointestinal (GI) parameter for 1 drug: simulated GI contractions on nifedipine release (in 2 extended release solid oral formulations). The 60 mg nifedipine osmotic pump product A, and polymer matrix-based products B and C were examined in the study. An in-house dissolution system was used to simulate various levels of GI contractions on tested samples, and to monitor changes of sample mechanical properties during dissolution testing. The results show that the polymer matrix-based formulation failed to provide controlled release when simulated GI contraction was above 100 g of force. The method may be useful for polymer matrix-based products to assess potential formulation-related interactions with the GI tract during in vivo drug dissolution.

Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets.

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products.

Dissolution Test of Tacrolimus Capsule: Effects of Filtration and Glass Adsorption.

Tacrolimus is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Dissolution tests are widely used to evaluate drug product quality and performance. Analysis of tacrolimus during dissolution testing is sensitive to several factors, such as sample solution storage time and container material. The filtration process, tacrolimus glass adsorption, and sample solution storage time are found to impact the tacrolimus dissolution results. Based on observations in this work, the use of G4 or equivalent filter flush before collection and polypropylene test tubes or vials instead of glass test tubes or vials are recommended for tacrolimus drug product dissolution test.

Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing.

BACKGROUND: Orally administered medications in extended-release (ER) dosage forms continue to play a pivotal role in the treatment of various central nervous system disorders. For certain ER dosage forms, pharmaceutical scientists have been familiar with the passage of intact tablet-like objects in patients' feces after administration of ER tablets or capsules based on water-insoluble or slowly dissolving excipients. Nevertheless, because of lack of awareness of the "ghost pill" phenomenon, anxiety has ensued among some patients and clinicians, who have less understanding of how drugs are released from these tablets once ingested. It has been brought to the attention of the US Food and Drug Administration (FDA) that epilepsy patients administered with Teva's levetiracetam ER tablets have noticed intact tablets in their stools and been concerned that they were not getting the needed dose of the drug. In response to neurologists' clinical reporting, the FDA has conducted investigations to confirm a minimal risk of incomplete drug release of Teva's drug product. OBJECTIVE: The objective of this study was to evaluate the risks of incomplete drug release associated with the passing of intact levetiracetam ER tablets, by conducting in vitro dissolution testing. METHODS: Dissolution testing of Teva's drug product was performed in accordance with the US Pharmacopeia monograph for levetiracetam ER tablets in phosphate buffer and bio-relevant buffers at different pH values. In addition, dissolution testing was conducted with split and crushed tablets. At the end of the dissolution testing, all samples were visually inspected for any undissolved pieces. RESULTS: Approximately 90 % of levetiracetam had been released in all dissolution media after 8 h of dissolution. The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media. The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets. CONCLUSION: On the basis of these findings, Teva's levetiracetam ER tablets may appear intact in the stools but have released the drug successfully. The FDA has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost pills in their stools may impetuously crush or split the tablets of subsequent doses on their own, healthcare providers should instruct patients to swallow whole tablets throughout the treatment, in accordance with the drug label.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.

Mathematical modeling of variables involved in dissolution testing.

Dissolution testing is an important technique used for development and quality control of solid oral dosage forms of pharmaceutical products. However, the variability associated with this technique, especially with USP apparatuses 1 and 2, is a concern for both the US Food and Drug Administration and pharmaceutical companies. Dissolution testing involves a number of variables, which can be divided into four main categories: (1) analyst, (2) dissolution apparatus, (3) testing environment, and (4) sample. Both linear and nonlinear models have been used to study dissolution profiles, and various mathematical functions have been used to model the observed data. In this study, several variables, including dissolved gases in the dissolution medium, off-center placement of the test tablet, environmental vibration, and various agitation speeds, were modeled. Mathematical models including Higuchi, Korsmeyer-Peppas, Weibull, and the Noyes-Whitney equation were employed to study the dissolution profile of 10 mg prednisone tablets (NCDA #2) using the USP paddle method. The results showed that the nonlinear models (Korsmeyer-Peppas and Weibull) accurately described the entire dissolution profile. The results also showed that dissolution variables affected dissolution rate constants differently, depending on whether the tablets disintegrated or dissolved.

Effects of vessel geometric irregularity on dissolution test results.

Dissolution testing of pharmaceutical products is an important technique used extensively for both product development and quality control, but there are many variables that can affect dissolution results. In this study, the effect of the inner shape of standard 1-L dissolution vessels on drug dissolution results was investigated. The geometric dimensions and irregularities of commercially available vessels (obtained from four different manufacturers) were examined using a three-dimensional video-based measuring machine (VMM). The same analyst, dissolution test assembly, and experimental conditions were used for dissolution testing involving 10 mg of prednisone tablets (NCDA #2) with dissolution apparatus 2 (paddle). Mechanical calibration of the dissolution apparatus was performed prior to dissolution testing with each set of vessels. Geometric characteristics varied within and among the sets of vessels, but the overall averages and standard deviations of dissolution results (six vessels) showed no statistical significant differences among the vessel sets. However, some dissolution differences were noted when comparing individual vessels. With these types of comparisons, the vessel concentricity, sphericity, and radius of sphere were found to possibly influence the amount of prednisone dissolved, but flatness of vessel flange, cylindricity, and circularity showed no effect on dissolution results. The study shows that VMM is a technique that could be used to qualify dissolution vessels.

Vibration effects of lab equipment on dissolution testing with USP paddle method.

Environmental vibration induced by laboratory equipment, building construction, or even by the analysts themselves is one of the more complicated factors affecting dissolution testing. It is difficult to control and/or calibrate by mechanical means or performance-based methods. In this study, dissolution apparatus vibration levels were measured in the frequency range from 10 to 270 Hz along all three axes using commercially available, single-axis accelerometers. The vibration distribution on the dissolution vessel plate was mapped, and acceleration was subsequently measured during dissolution runs involving NCDA#2 (10 mg prednisone) tablets using the paddle method. Several types of laboratory equipment were used to induce vibration during dissolution testing and vibration levels along the X-, Y-, and Z-axes of the vessel plate were measured in an attempt to establish possible correlation with dissolution results. In the frequency range studied, root mean square (RMS) acceleration values above 0.01 g, in either vertical or horizontal direction, typically affected dissolution results.