Drug dissolution and transit in a heterogenous gastric chyme after fed administration: Semi-mechanistic modeling and simulations for an immediate-release and orodispersible tablets containing a poorly soluble drug.

Mathematical models that treat the fed stomach content as a uniform entity emptied with a constant rate may not suffice to explain pharmacokinetic profiles recorded in clinical trials. In reality, phenomena such as the Magenstrasse or chyme areas of different pH and viscosity, play an important role in the intragastric drug dissolution and its transfer to the intestine. In this study, we investigated the data gathered in the bioequivalence trial between an immediate-release tablet (Reference) and an orally dispersible tablet (Test) with a poorly soluble weak base drug administered with or without water after a high-fat high-calorie breakfast. Maximum concentrations (Cmax) were significantly greater after administering the Reference product than the Test tablets, despite similar in vitro dissolution profiles. To explain this difference, we constructed a novel semi-mechanistic IVIVP model including a heterogeneous gastric chyme. The drug dissolution in vivo was modeled from the in vitro experiments in biorelevant media simulating gastric and intestinal fluids in the fed state (FEDGAS and FeSSIF). The key novelty of the model was separating the stomach contents into two compartments: isolated chyme (the viscous food content) that carries the drug slowly, and aq_chyme open for rapid Magenstrasse-like routes of drug transit. Drug distribution between these two compartments was both formulation- and administration-dependent, and recognized the respective drug fractions from the clinical pharmacokinetic data. The model's assumption about the nonuniform mixing of the API with the chyme, influencing differential drug dissolution and transit kinetics, led to simulating plasma concentration profiles that reflected well the variability observed in the clinical trial. The model indicated that, after administration, the Reference product mixes to a greater extent with aq_chyme, where the released drug dissolves better and transfers faster to the intestine. In conclusion, this novel approach underlines that diverse gastric emptying of different oral dosage forms may significantly impact pharmacokinetics and affect the outcomes of bioequivalence trials.

Conjunction of semi-mechanistic in vitro-in vivo modeling and population pharmacokinetics as a tool for virtual bioequivalence analysis - a case study for a BCS class II drug.

Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator's plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial's failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development.

Exploiting synergistic effects of brittle and plastic excipients in directly compressible formulations of sitagliptin phosphate and sitagliptin hydrochloride.

Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug substance(s) with excipients followed by compressing the powder mixture into tablets. In this study, immediate-release film-coated tablets containing either Sitagliptin phosphate or Sitagliptin hydrochloride were developed using DC technique. After establishing the optimum ratio of ductile and brittle excipients, five formulations were compressed into tablets using a rotary press and finally film coated. Both powders and tablets were examined by standard pharmacopoeial methods. It has been shown that the simultaneous use of excipients with different physical properties, i.e. ductile microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate, produces a synergistic effect, allowing preparation of Sitagliptin DC tablets with good mechanical strength (tensile strength over 2 N/mm2), rapid disintegration (shorter than 2 min), and fast release of the drug substance (85% of the drug is dissolved within 15 min). It was found that the type of calcium phosphate excipient used had a large effect on the properties of the sitagliptin tablets. All formulations developed showed good chemical stability, even when stored under stress conditions (50 °C/80% RH).

Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets.

Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique.

Application of Dominance-Based Rough Set Approach for Optimization of Pellets Tableting Process.

Multiple-unit pellet systems (MUPS) offer many advantages over conventional solid dosage forms both for the manufacturers and patients. Coated pellets can be efficiently compressed into MUPS in classic tableting process and enable controlled release of active pharmaceutical ingredient (APIs). For patients MUPS are divisible without affecting drug release and convenient to swallow. However, maintaining API release profile during the compression process can be a challenge. The aim of this work was to explore and discover relationships between data describing: composition, properties, process parameters (condition attributes) and quality (decision attribute, expressed as similarity factor f2) of MUPS containing pellets with verapamil hydrochloride as API, by applying a dominance-based rough ret approach (DRSA) mathematical data mining technique. DRSA generated decision rules representing cause-effect relationships between condition attributes and decision attribute. Similar API release profiles from pellets before and after tableting can be ensured by proper polymer coating (Eudragit® NE, absence of ethyl cellulose), compression force higher than 6 kN, microcrystalline cellulose (Avicel® 102) as excipient and tablet hardness ≥42.4 N. DRSA can be useful for analysis of complex technological data. Decision rules with high values of confirmation measures can help technologist in optimal formulation development.

The use of novel tools for the assessment of powders and granules flow properties and for the analysis of minitablets compression process.

Objective: The purpose of this study was to apply the rheological measurements to assess the flow properties of powders and granules and to compare the results with the standard pharmacopeial tests. Quality by design approach was utilized to better understand the compression of the solids into minitablets.Significance: Insights are provided regarding the methodology of rheological properties of powders and granules using powder flow analyzer (PFA). The 'six sigma' approach was presented as a tool for assessment of the minitablets manufacturing process.Methods: Pharmacopeial methods and rheological tests using PFA were performed to assess the flow properties of designed powder and fractionated granule mixtures - placebo and with benzodiazepines. Compression of 2.5 and 3 mm minitablets was carried out and the compression force registered during the process and weight uniformity were statistically analyzed by calculating the capability indices.Results: The flow rate measurement and cohesion test (PFA test) resulted in the best differentiation between mixtures. Higher values of capability indices were obtained for processes in which granule mixtures with better flow properties were compressed and 3 mm minitablets were produced and the usefulness of QbD tools in assessment of minitablets compression process was confirmed.Conclusion: Performed study showed that the flow properties are the critical quality attributes determining the performance of minitablets compression. The cohesion test is the most discriminative to distinguish the analyzed mixtures. Capability indices can be used to assess the manufacturing process as a useful tool in pharmaceutical development of minitablets.

Optimization of pellets manufacturing process using rough set theory.

Pharmaceutical pellets are spherical agglomerates manufactured in extrusion/spheronization process. The composition of the pellets, the amount of active pharmaceutical ingredient (API) and the type of used excipients have an influence on the shape and quality of dosage form. A proper quality of the pellets can also be achieved by identifying the most important technological process parameters. In this paper, a knowledge discovery method, called dominance-based rough set approach (DRSA) has been applied to evaluate critical process parameters in pellets manufacturing. For this purpose, a set of condition attributes (amount of API; type and amount of excipient used; process parameters such as screw and rotation speed, time and temperature of spheronization) and a decision attribute (quality of the pellets defined by the aspect ratio) were used to set up an information system. The DRSA analysis allowed to induce decision rules containing information about process parameters which have a significant impact on the quality of manufactured pellets. Those rules can be used to optimize the process of pellets manufacturing.

Technology of eye drops containing metronidazole.

The aim of the studies was to determine the stability of metronidazole using UV spectrophotometric method in 0.5% w/w eye drops which were prepared under aseptic conditions and thermally sterilized. 0.9% solution of NaCl, 5% glucose and phosphate buffers of pH 6.97 and 6.81 were used as the solvents of metronidazole in the drops. Thiomersal and phenylmercuric borate were used to preserve the drops. The viscosity of the eye drops was increased using the solution of polyvinyl alcohol. The drops were stored in tightly closed glass infusion bottles, protected from light. For the stability of analysis a long-term assay was used under controlled conditions following the requirements of ICH, i.e., the time of storage was 24 months at the constant temperature of 25 +/- 2 degrees C and constant humidity of 60% +/- 2% RH. The eye drops containing metronidazole were significantly physically and chemically stable: after 24 months of storage the metronidazole concentration in the drops was close to 100% of the initial concentration. The drops were colorless and transparent. Physical and chemical properties such as pH, osmotic pressure and viscosity underwent insignificant changes during the storage. The preservation test showed that the degree of reduction of the pharmacopeal strains of micro-organisms in freshly prepared drops and in those stored for 24 months at the temperature of 25 +/- 20 degrees C was in agreement with the requirements of Ph. Eur. 6.