Virginie Busignies

Curing of aqueous polymeric film coatings: Importance of the coating level and type of plasticizer.

The aim of this study was to better understand the effects of the curing conditions on the resulting drug release patterns from pellets coated with aqueous polymer dispersions. Diltiazem HCl was used as model drug, ethylcellulose as polymer, triethyl citrate (TEC), dibutyl sebacate (DBS), and distilled acetylated monoglycerides (Myvacet) as plasticizers. Interestingly, the effects of the curing conditions strongly depended on the coating level and the type of plasticizer: in the case of TEC, the drug release rate monotonically decreased with increasing harshness of the curing conditions (time, temperature, and relative humidity), irrespective of the coating level. In contrast, in the case of DBS and Myvacet, this type of relationship was only observed at low coating levels (5%). At intermediate coating levels (around 7.5%), the curing conditions had virtually no effect on drug release. At high coating levels (10%), the release rate initially increased and then decreased with increasing harshness of the curing conditions. This more complex behavior might be attributable to the superposition of two competing phenomena: improved film formation and drug migration into the polymeric membrane. Furthermore, it could be shown that the type of plasticizer had a major effect on drug release in not fully coalesced and equilibrated film coatings, whereas the release profiles were similar for all plasticizers in the case of completely formed and equilibrated film coatings. Importantly, the latter systems were stable for long term even during storage under stress conditions.

Measurements of elastic moduli of pharmaceutical compacts: A new methodology using double compaction on a compaction simulator

The elastic properties of pharmaceutical powders play an important role during the compaction process. The elastic behavior can be represented by Youngs modulus (E) and Poissons ratio (v). However, during the compaction, the density of the powder bed changes and the moduli must be determined as a function of the porosity. This study proposes a new methodology to determine E and v as a function of the porosity using double compaction in an instrumented compaction simulator. Precompression is used to form the compact, and the elastic properties are measured during the beginning of the main compaction. By measuring the axial and radial pressure and the powder bed thickness, E and v can be determined as a function of the porosity. Two excipients were studied, microcrystalline cellulose (MCC) and anhydrous calcium phosphate (aCP). The values of E measured are comparable to those obtained using the classical three-point bending test. Poissons ratio was found to be close to 0.24 for aCP with only small variations with the porosity, and to increase with a decreasing porosity for MCC (0.23-0.38). The classical approximation of a value of 0.3 for ν of pharmaceutical powders should therefore be taken with caution.

Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets

The effect of the elasticity of various pharmaceutical materials on the interfacial adhesion in bilayer tablets was investigated. The elastic properties of five pharmaceutical products were characterized by their total elastic recovery. To test the interfacial strength of the bilayer tablets a new flexural test was proposed. Thanks to the test configuration, the experimental breaking force is directly correlated with the interfacial layer strength. Depending on the materials, the fracture occurred over the interface or in one of the two layers. In most cases, the highest breaking forces were obtained when the materials had close elastic recovery. On the contrary, for materials with different elastic recovery, the breaking forces were reduced. The observed changes in the interfacial mechanical strength were statistically analyzed. Such an approach has an importance in the growing interest in the Quality by Design (QbD) concept in pharmaceutical industry.

Changes in the specific surface area of tablets composed of pharmaceutical materials with various deformation behaviors

Objective: The aim of this work is to study the effect of compaction on the specific surface area of tablets composed of various pharmaceutical materials (microcrystalline cellulose, lactose, and anhydrous calcium phosphate) compacted under seven degrees of compaction pressure. Methods: In a first part, the influence of the deformation behavior of the compacted materials on the evolution of the specific surface area is observed. In a second part, the brittle and ductile abilities of the materials are calculated using the specific surface area values. The experimental results are used to calculate the number and the force of interparticulate bonds inside the tablet.Results and Discussion: Tablets made of microcrystalline cellulose, which deform plastically, have specific surface areas that fall under pressure. In the case of lactose, the tablet specific surface area first increases to reach a maximum value at a pressure of 150 MPa. At higher pressure, however, the specific surface area decreases. The specific surface area of tablets composed of anhydrous calcium phosphate consistently increases, whatever the compaction pressure applied. Moreover, the evolution of the specific surface area is correlated with the tensile strength of the corresponding tablets. The number and the force of interparticulate bonds make it possible to classify the materials according to their deformation behavior and to quantify their ability to form cohesive tablets.

On the Links Between Elastic Constants and Effective Elastic Behavior of Pharmaceutical Compacts: Importance of Poisson's Ratio and Use of Bulk Modulus

The elastic properties of pharmaceutical powders and compacts are of great interest to understand the complex phenomena that occur during and after the tableting process. The elastic recovery after compression is known to be linked with adverse phenomena such as capping or delamination of tablets. Classically, the elastic behavior is modeled using linear elasticity and is characterized using only Youngs modulus (E), often by using a value extrapolated at zero porosity. In this work, four pharmaceutical products were studied. The elastic behavior of compacts obtained using a large range of applied pressure was characterized. First, it was found more suitable to use apparent elastic moduli than extrapolations at zero porosity. Then, the results indicate that there was not always a good correlation between the values of Youngs modulus and the actual elastic recovery of the compacts. Poissons ratio (v), which differs from one product to another and is porosity-dependent, must be taken into account. Finally, the bulk modulus (K), which combines E and v, was shown to be well correlated with the elastic recovery of the compacts and can be considered as a relevant parameter to characterize the elastic behavior of pharmaceutical compacts.

The Effects of Relative Humidity and Super-Disintegrant Concentrations on the Mechanical Properties of Pharmaceutical Compacts

The influence of the composition and the relative humidity on the properties of pharmaceutical compacts prepared from mixtures of three excipients and three super-disintegrants was evaluated. Various amounts of super-disintegrant and different conditions of relative humidity during the storage were used to study mechanistically the disintegration process and to connect it to compacts mechanical properties. Three point single beam test was used to measure tensile strength and Youngs modulus of compacts containing various amount of disintegrant and stored under various relative humidity. The presence of moisture within pharmaceutical compacts containing a disintegrant influences drastically their mechanical properties. Then, the results are related to micro-cracks visualized by MEB.

Comparison of different failure tests for pharmaceutical tablets: Applicability of the Drucker–Prager failure criterion

Several tests can be used to study the strength of pharmaceutical tablets. Equations exist in the literature to transform the failure force measured into a failure stress which can be considered as a characteristic of the strength of the material. For each failure test, the stress state at failure is different, and as a consequence, the failure stresses obtained are also different. It would thus be interesting to find a failure criterion to unify the different results. In this study four different tests were performed on pharmaceutical compacts of various densities: diametral compression, three-point flexure, biaxial flexure and uniaxial compressive tests. The Drucker-Prager criterion was tested as a possible fracture envelope. The results showed that this criterion is well suited to explain the failures obtained by diametral compression, three-point flexure and biaxial flexure. Nevertheless, for the uniaxial compressive test, the use of this criterion led to a significative underestimation of the experimental value of the failure stress. As a consequence, the Drucker-Prager criterion must be used with caution and is not able to explain all the failures that can occur in a pharmaceutical compact.

Mechanistic Approach to Stability Studies as a Tool for the Optimization and Development of New Products Based on L. rhamnosus Lcr35® in Compliance with Current Regulations

Probiotics are of great current interest in the pharmaceutical industry because of their multiple effects on human health. To beneficially affect the host, an adequate dosage of the probiotic bacteria in the product must be guaranteed from the time of manufacturing to expiration date. Stability test guidelines as laid down by the ICH-Q1A stipulate a minimum testing period of 12 months. The challenge for producers is to reduce this time. In this paper, a mechanistic approach using the Arrhenius model is proposed to predict stability. Applied for the first time to laboratory and industrial probiotic powders, the model was able to provide a reliable mathematical representation of the effects of temperature on bacterial death (R2>0.9). The destruction rate (k) was determined according to the manufacturing process, strain and storage conditions. The marketed product demonstrated a better stability (k = 0.08 months−1) than the laboratory sample (k = 0.80 months−1). With industrial batches, k obtained at 6 months of studies was comparable to that obtained at 12 months, evidence of the model’s robustness. In addition, predicted values at 12 months were greatly similar (±30%) to those obtained by real-time assessing the model’s reliability. This method could be an interesting approach to predict the probiotic stability and could reduce to 6 months the length of stability studies as against 12 (ICH guideline) or 24 months (expiration date).

Anisotropic Porous Structure of Pharmaceutical Compacts Evaluated by PGSTE-NMR in Relation to Mechanical Property Anisotropy

ABSTRACTPurposeThe pore space anisotropy of pharmaceutical compacts was evaluated in relation to the mechanical property anisotropy.MethodsThe topology and the pore space anisotropy were characterized by PGSTE-NMR measurements. Parallelepipedical compacts of anhydrous calcium phosphate (aCP) and microcrystalline cellulose (MCC) were tested on top, bottom and side faces. A microindentation and three-point single beam tests were used to measure Brinell hardness, tensile strength and Young’s modulus. All the data were submitted to a statistical analysis to test for significance.ResultsThe porous structure of MCC compacts was anisotropic, contrary to those of aCP. The analysis of the pore space by PGSTE-NMR method showed that its structural anisotropy was controlled by the behaviour under compaction of the excipients. At the same time, the Young’s modulus and the tensile strength were the same whatever the direction of testing. For the aCP compacts, all the faces had the same Brinell hardness. With MCC compacts, only the bottom face showed a lower Brinell hardness.ConclusionsExcept for Brinell hardness measured on MCC compacts, the tested samples were characterized by anisotropic mechanical properties when its porous structures were sometimes anisotropic. Then, there is not a straight link between porosity anisotropy and mechanical properties.