Functionality of disintegrants with different mechanisms after roll compaction.

The aim of this study was to investigate the functionality of two disintegrants (crospovidone and croscarmellose sodium) in tablet formulations processed via roll compaction and subsequent tableting. The influence of different fillers and the effect of sodium lauryl sulfate on the disintegration process were studied using full factorial design. For a direct comparison of disintegrant functionality, the center point formulations were manufactured via direct compression. Tablet characteristics, such as tensile strength, solid fraction, disintegration time and mechanism, and dissolution profile were determined. The results allow the conclusion that the functionality of the disintegrants is impaired by dry granulation. Both the disintegration mechanism and the disintegration time were different when comparing tablets made after dry granulation and by direct compression. The effect was more pronounced on the functionality of crospovidone than on that of croscarmellose sodium. In addition, sodium lauryl sulfate showed a notable influence on all tablet properties due to its lubricating effect. The variation of the filler also had a remarkable effect on the tablet characteristics. The results link excipient functionality to drug product properties depending on the applied manufacturing process and could contribute to extend the Manufacturing Classification System to excipient characteristics.

Stability and compatibility of Basmisanil granules co-administered with soft food.

Co-administration of solid oral dosage forms with soft food or beverages is commonly used to facilitate administration and to improve compliance in the paediatric and geriatric population and in patient groups with swallowing difficulties. The present case study was conducted to investigate the compatibility, stability and dissolution of Basmisanil administered as granules mixed with different soft food matrices. The data were generated to justify dosing instructions, according which Basmisanil should be sprinkled on or mixed with one tablespoon of soft food to aid swallowing. Different soft food types were selected to cover a broad range of various food components (e.g. fat, protein, carbohydrates, fiber and water) and pH. Active content and degradation products of the active substance were determined after mixing the granules with the semisolid food matrix and after two hours of storage under ambient conditions, respectively. In-vitro dissolution tests of granule/food mixtures were also conducted. Furthermore, the stability of the API polymorph was evaluated. Basmisanil shows good chemical stability when the granules are mixed with soft food and consumed within two hours. No polymorphic conversion (anhydrate to monohydrate) could be detected in the granule/food mixtures after preparation and after storage up to 24 h. The in-vitro dissolution of the API from the granules was not adversely affected by the presence of the food matrix. All results were comparable regardless of the tested food matrix. The results do not prohibit the administration of the granules with soft food to the patient.

Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing.

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.

Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing.

The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies. Finally, an in vitro-in vivo correlation (IVIVC) model was developed using conventional and mechanistic deconvolution methods for comparison. The GastroPlus model accurately simulated oral Basmisanil exposure from tablets and granules formulations containing micronized drug. Absorption of oral doses below 200 mg was mostly dissolution rate-limited and thus particularly sensitive to formulation properties. Indeed, reduced exposure was observed for a 120-mg film-coated tablet and the slower dissolution rate measured in biorelevant media was attributed to differences in drug load. This hypothesis was confirmed when Raman imaging showed that the percolation threshold was exceeded in this formulation. This biorelevant dissolution method clearly differentiated between the formulations and was used to develop a robust IVIVC model. The study demonstrates the applicability and impact of mechanistic absorption modelling and biopharmaceutical in vitro tools for rational drug development.

Effect of additives on isothermal crystallization kinetics and physical characteristics of coconut oil.

The effect of lauric acid and low-HLB sucrose esters (L-195, S170) on the isothermal crystallization of coconut oil was investigated by differential scanning calorimetry. The fundamental crystallization parameters, such as induction time of nucleation and crystallization rate, were obtained by using the Gompertz equation. The Gibb's free energy of nucleation was calculated via the Fisher-Turnbull equation based on the equilibrium melting temperature. All additives, investigated in this work, proved to have an inhibition effect on nucleation and crystallization kinetics of coconut oil. Our results revealed that the inhibition effect is related to the dissimilarity of the molecular characteristics between coconut oil and the additives. The equilibrium melting temperature (T(m) degrees ) of the coconut oil-additive mixtures estimated by the Hoffman-Weeks method was decreased with the addition of lauric acid and increased by using sucrose esters as additives. Micrographs showing simultaneous crystallization of coconut oil and lauric acid indicated that strong molecular interaction led to the increase in lamellar thickness resulting in the T(m) degrees depression of coconut oil. The addition of L-195 modified the crystal morphology of coconut oil into large, dense, non-porous crystals without altering the polymorphic occurrence of coconut oil. The enhancement in lamellar thickness and crystal perfection supported the T(m) degrees elevation of coconut oil.

Water sorption behavior and swelling characteristics of starches subjected to dielectric heating.

The aim of this study was to investigate the effects of microwave irradiation and storage on the moisture content, adsorption behavior and swelling properties of potato (B-type) and maize starches (A-type). Volumetric heating resulted in reversible moisture loss from both types of samples. The crystallinity of potato starch was decreased, whereas its water retention capacity and swelling power were increased irreversibly, and its swelling capacity was increased reversibly by the thermal process applied. The corresponding parameters of maize starch were not influenced significantly by dielectric heating; this may be related to its special structure resulting in the thermal resistance of this polymer. Our results allow the conclusion that microwave irradiation offers an appropriate and selective alternative for the physicochemical modification of potato starch. In consequence of its low susceptibility to thermal processes, maize starch may be used for the microwave drying of pharmaceutical formulations containing starch.

[Determination of the gelatinization temperature of starches via thermoanalytical and rheological methods]. / Keményítok gélesedési homérsékletenek meghatározása termoanalitikai es reológiai módszerekkel.

This work provides a short review concerning the measuring techniques frequently applied to characterize the gelatinization behaviour of starches. The aim of the experiments was to determine the gelatinization temperatures of maize (A-type) and potato (B-type) starches via isothermal microcalorimetry and rheological methods (rotational viscosimetry and dynamic oscillatory testing). A significant difference was observed between the gelatinization temperatures of the aqueous starch suspensions, which can be attributed to the structural differences between A-type and B-type starches. Comparison of the applied measuring methods revealed a close correlation between the experimental data obtained by isothermal microcalorimetry and oscillatory testing, while rotational viscosimetry overestimated the gelatinization temperature. Additionally dynamic oscillatory tests provided valuable information not only on the gelatinization point, but also on the pasting temperature of the starch suspensions.

[Use of mercury porosimetry, assisted by nitrogen adsorption in the investigation of the pore structure of tablets]. / Higanyos porozimetria és nitrogén adszorpció együttes alkalmazása tabletták pórusszerkezetének vizsgálatában.

The microstructure of pharmaceutical solid dosage forms (porosity, pore volume-size distribution, specific surface area) can be investigated by different methods. Mercury porosimetry and nitrogen gas adsorption have been widely used to characterize the pore structure of tablets because these methods enable the determination of porosity and pore size distribution in one step. The two techniques are based on different physical interactions and cover specific ranges of pore size. Mercury porosimetry determines mesopores and macropores, whereas gas adsorption covers the micropore range. The aim of this study was to investigate the relationship between the compression force and the structure of tablets containing theophylline. The porosity parameters determined with mercury porosimetry and nitrogen adsorption were compared. The results indicated a good correlation between the applied compression forces and the porosity parameters of the tablets. The pore volume-size distributions, the pore size frequencies and the specific surface areas obtained with mercury porosimetry and nitrogen adsorption were not equal, which can be attributed to the different measurement ranges and to the complexity of the pore structures. Our results allow the conclusion that mercury porosimetry, assisted by nitrogen adsorption as a complementary technique, is an acceptable method to achieve a proper characterization of the internal structure of tablets.

Microwave processing of natural biopolymers--studies on the properties of different starches.

In this study, the influence of microwave irradiation on some physico-chemical properties and several pharmaceutical technological parameters of potato and maize starches was investigated. Changes in their habits were observed and decrease in moisture contents caused by the electromagnetic irradiation was determined. The crystalline structures and the micromorphological parameters of the starches were affected by microwave irradiation in different ways depending on the botanical origin of the samples. The tensile strengths of the compacts containing starches were decreased, their wetting properties were enhanced by the thermal process applied. Furthermore, microwave irradiation reduced the surface free energy and the polarity of the compacts significantly. Samples treated by conventional heating were used to compare the effects of microwave irradiation on the examined properties and parameters of these starches.