Genesis, mechanism, and avoidance of cosmetic coating defects - An industrial case study.

Film-coated tablets as solid oral dosage forms are a well-accepted way of administering drugs but are not without specific challenges during manufacturing. One relevant criterion of the final product is the visual integrity and therewith, the absence of cosmetic optical defects such as edge chipping. The aim of the present study was to examine the origin of those edge chipping defects, which were observed during commercial manufacturing of film-coated tablets, and to provide recommendations for process optimization to reduce the defect occurrence. The unraveling of the herein described phenomenon necessitated an interplay of in-depth material characterization, discrete element modeling (DEM) as well as an in-house developed optical measurement system for the automated quantification of tablet defects. As a result of this investigation, the automatic unloading step after the tablet coating process was identified as the most critical step for the occurrence of chipping defects and a replacement by manual unloading was proposed to reduce the defect propensity. The recommended optimization was subsequently confirmed in several manufacturing runs and a reduction of defect propensity by a factor of 5 was observed, highlighting the relevance and the impact of the performed thorough investigation.

Impact of incorporated drugs on material properties of amorphous solid dispersions.

Formulation development of amorphous solid dispersions (ASD) still is challenging although several poorly water-soluble drugs have been marketed using this technique. During development of novel drugs, the selection of the preparation technique and polymer matrix is commonly performed for the certain drug via screening tools. However, if general trends regarding material properties are to be investigated, this approach is not beneficial, although often utilized in literature. The main component of the ASD usually is the polymer and thus it predominantly determines the material properties of the system. Therefore, to study the impact of different drugs and their drug loads on mechanical properties and wettability, three poorly soluble model drugs with drug loads ranging from 10% to 40% were incorporated into copovidone via hot-melt extrusion. The obtained extrudates were subsequently characterized regarding mechanical properties by applying diametral compression test and nanoindentation and the results were compared to the performance during tablet compression. Incorporation of all tested drugs resulted in a similar increase in brittleness of the ASDs, whereas the Young's modulus and hardness changed differently in dependence of the incorporated drug. These observations correlated well with the performance during tablet compression and it was concluded, that the brittleness seemed to be the predominant factor influencing the compression behavior of copovidone-based ASDs. Furthermore, the degree of water absorption and wettability was assessed by applying dynamic vapor sorption experiments and contact angle measurements. Here, the incorporated drugs impacted the contact angle to different degrees and a strong correlation between the contact angle and disintegration time was observable. These results highlight the importance of thorough characterization of the ASDs as it helps to predict their performance during tablet compression and thus facilitates the optimal selection of excipients.

Impact of structural relaxation on mechanical properties of amorphous polymers.

Fusion based methods, such as hot-melt extrusion, are a common way of preparing amorphous solid dispersions. Since the amorphous glass, however, is not in a configurational equilibrium, the molecular arrangement of the obtained material can differ in dependence of the preparation conditions. Although the changes in the configuration of an amorphous material, which are commonly referred to as structural relaxation or physical aging, are well investigated, the impact on mechanical properties of amorphous solid dispersions have widely been neglected so far. The presented study investigated copovidone as a model polymer commonly used in amorphous solid dispersions and revealed that structural relaxation was already introduced into the polymer during hot-melt extrusion while its degree was cooling rate dependent. The degree of structural relaxation significantly affected the mechanical properties of copovidone as assessed by diametral compression tests, macroindentation and nanoindentation. An increase in Young's modulus and indentation hardness was observable with a higher degree of structural relaxation, which, during tablet compression, translated into tablets with significantly lower tensile strength. Furthermore, evaluation of the force-displacement curves during tablet compression revealed a decreased proportion of irreversible deformation with higher degree of structural relaxation correlating well with the increased indentation hardness during macroindentation. Thus, understanding structural relaxation and its impact on material properties is of utmost importance to assess the processability and compaction performance of amorphous solid dispersions in dependence of their preparation conditions and thermal history.

Determination of the Structural Relaxation Enthalpy Using a Mathematical Approach.

Structural relaxation is a well-known phenomenon in amorphous materials such as amorphous solid dispersions. It is generally understood as a measure for molecular mobility and has been shown to impact certain material properties such as the dissolution rate. Several quantification methods to evaluate structural relaxation using differential scanning calorimetry have been proposed in the past, but all approaches exhibit disadvantages. In this work, a mathematical model was developed and fitted to calorimetric data enabling the analysis of the structural relaxation enthalpy by separating the structural relaxation peak from the underlying glass transition. The proposed method was validated using a parameter sensitivity analysis. Differently stressed amorphous samples were analyzed applying the new model and the results were compared to commonly applied quantification methods in literature. The proposed method showed high robustness and accuracy and overcame the observed disadvantages of the established methods. The heating rate dependence of the calculated structural relaxation enthalpy was in accordance with theoretical considerations of previous studies, supporting the validity of the results. Thus, the proposed model is suitable to accurately quantify the degree of structural relaxation and should be a valuable tool for further investigations regarding the impact of structural relaxation on material properties.

Michael acceptor containing drugs are a novel class of 5-lipoxygenase inhibitor targeting the surface cysteines C416 and C418.

Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting catalytically with cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators. We screened a large library of naturally derived and synthetic electrophilic compounds to investigate whether other types of Michael acceptor containing drugs suppress 5-LO enzyme activity. The activity was measured by assessing the effect on the 5-LO product formation of intact human polymorphonuclear leukocytes. We demonstrated that a number of structurally different compounds were suppressive in the activity assays and showed that Michael acceptors of the quinone and nitro-alkene group produced the strongest inhibition of 5-LO product formation. Reactivity with the catalytically relevant cysteines 416 and 418 was confirmed using mutated recombinant 5-LO and mass spectrometric analysis (MALDI-MS). In the present study, we show for the first time that a number of well-recognized naturally occurring or synthetic anti-inflammatory compounds carrying a Michael acceptor, such as thymoquinone (TQ), the paracetamol metabolite NAPQI, the 5-LO inhibitor AA-861, and bardoxolone methyl (also known as RTA 402 or CDDO-methyl ester) are direct covalent 5-LO enzyme inhibitors that target the catalytically relevant cysteines 416 and 418.