Jarkko Ketolainen

Predicting the Formation and Stability of Amorphous Small Molecule Binary Mixtures from Computationally Determined Flory−Huggins Interaction Parameter and Phase Diagram

The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.

Effects of grinding and compression on crystal structure of anhydrous caffeine

Abstract The extent of the polymorphic transformation of anhydrous caffeine has been studied as a function of grinding time and compression pressure by using quantitative X-ray diffraction analysis. The measurements show that both grinding and compression induce the transformation from the metastable form I into the stable form II. The transformation can be observed even after 1 min grinding or by using a compression pressure of about 50 MPa in tableting. The degree of transformation is greater near the surface than in the middle part of the tablet.

Visualization and understanding of the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging.

Over the last decade, there has been increased interest in the application of twin screw granulation as a continuous wet granulation technique for pharmaceutical drug formulations. However, the mixing of granulation liquid and powder material during the short residence time inside the screw chamber and the atypical particle size distribution (PSD) of granules produced by twin screw granulation is not yet fully understood. Therefore, this study aims at visualizing the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging. In first instance, the residence time of material inside the barrel was investigated as function of screw speed and moisture content followed by the visualization of the granulation liquid distribution as function of different formulation and process parameters (liquid feed rate, liquid addition method, screw configuration, moisture content and barrel filling degree). The link between moisture uniformity and granule size distributions was also studied. For residence time analysis, increased screw speed and lower moisture content resulted to a shorter mean residence time and narrower residence time distribution. Besides, the distribution of granulation liquid was more homogenous at higher moisture content and with more kneading zones on the granulator screws. After optimization of the screw configuration, a two-level full factorial experimental design was performed to evaluate the influence of moisture content, screw speed and powder feed rate on the mixing efficiency of the powder and liquid phase. From these results, it was concluded that only increasing the moisture content significantly improved the granulation liquid distribution. This study demonstrates that NIR chemical imaging is a fast and adequate measurement tool for allowing process visualization and hence for providing better process understanding of a continuous twin screw granulation system.

Dehydration of theophylline monohydrate : a two step process

The physicochemical properties of theophylline monohydrate and anhydrous polymorphic form II were evaluated using crystallographic, calorimetric and computational methods. The heats of solution of theophylline monohydrate and its anhydrous form were 28.6 and 19.4 kJ/mol, respectively, and the heat of hydration of theophylline anhydrous was 12.2 kJ/mol, as determined by solution calorimetry. Dehydration of theophylline monohydrate was studied by DSC. Under closed, hermetic conditions, the heat of dehydration, 10.7 kJ/mol, was almost equal to the heat of hydration. Under open conditions, the measured heat of dehydration was 47.3 kJ/mol. The dehydration phenomenon was examined also by molecular modelling and the computed heat changes were equal to those determined experimentally. The obtained experimental and theoretical results indicated that the monohydrate-anhydrate transition of theophylline is energetically reversible. Under closed conditions and in the aqueous media, the reversible monohydrate-anhydrate transition comprised only the dehydration or hydration step and the heat of transitions were considerably lower than under open conditions. Under open conditions, the dehydration of theophylline monohydrate proceeds in two steps even though the steps are overlapping. The first step is dehydration and the second is evaporation of the loosened crystal water.

Effects of physical properties for starch acetate powders on tableting

The aim of the study was to investigate particle and powder properties of various starch acetate powders, to study the effect of these properties on direct compression characteristics, and to evaluate the modification opportunity of physical properties for starch acetate powders by using various drying methods. At the end of the production phase of starch acetate, the slurry of starch acetate was dried using various techniques. Particle, powder, and tableting properties of end products were investigated. Particle size, circularity, surface texture, water content and specific surface area varied according to the particular drying method of choice. However, all powders were freely flowing. Bulk and tapped densities of powders varied in the range of 0.29 to 0.44 g/cm3 and 0.39 to 0.56 g/cm3, respectively. Compaction characteristics revealed that all powders were easily deformed under compression, having yield pressure values of less than 66 MPa according to Heckel analysis. All powders possessed a significant interparticulate bond-forming capacity during compaction. The tensile strength values of tablets varied between 10 and 18 MPa. In conclusion, physical properties of starch acetate could be affected by various drying techniques. A large specific surface area and water content above 4% were favorable properties by direct compression, especially for small, irregular, and rough particles.

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.

Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT)

Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI).

Temperature changes during tabletting measured using infrared thermoviewer

Abstract To observe the rise in temperature during tabletting an infrared thermoviewer was used together with an instrumented eccentric tablet press. To evaluate the tabletting process, temperatures measured from surfaces of recently ejected tablets were used together with energy parameters. Two direct compression excipients, plastically deforming microcrystalline cellulose and fragmenting dicalcium phosphate dihydrate, were tabletted. Due to differences in specific heat values, the temperature rise of the tablets was higher with microcrystalline cellulose than with dicalcium phosphate. Also more non-homogeneous particle shape and plastic deformation instead of fragmentation may have led to higher temperatures of microcrystalline cellulose tablets. For both test materials the temperature of the tablets rose with the compressional force whereas lubrication diminished the rise in temperature. Due to the non-homogeneous densification the highest temperature values were obtained at the centre of the upper surfaces of the tablets. After a short initial stabilization phase, the rise in tablet temperature became greatly dependent on the temperature increase of the powder in the hopper. From the energy parameter values, derived either from force and displacement data (mechanical energy), or from specific heat, temperature increase and tablet weight values (thermal energy), it was noted that the mechanical energy was very extensively converted to thermal energy. Thus, a permanent increase in energy content of powders by compression seemed to be small. The infrared thermoviewer was found to be an accurate and informative method for evaluating changes in the temperature and energy content of compressed powders during a dynamic tabletting process.

Detection of porosity of pharmaceutical compacts by terahertz radiation transmission and light reflection measurement techniques

We report on the non-destructive quantification of the porosity of pharmaceutical compacts (microcrystalline cellulose tablets) by using both optical and terahertz techniques. For the full analysis of the porosity of pharmaceutical tablets, the results obtained in both cases have shown that optical and terahertz techniques are complementary. The intrinsic refractive index of microcrystalline cellulose was estimated using the effective refractive index obtained from the time delay of the THz pulse together with the Bruggeman model for effective media. Once this intrinsic refractive index is known, the unknown porosity of the tablet can be estimated with the aid of the measured effective refractive index as well as the thickness of the pharmaceutical tablet. The method was tested using a set of thirteen tablets having different porosities. It is shown that the error in the estimation of the unknown tablets porosity is less than 1%. In addition, surface roughness was measured by using an optical interferometer and gloss by using a diffractive-optical-element based glossmeter. The measurement was achieved by scanning the tablets with a probe beam and detecting the reflected light. The surface roughness and gloss data show relatively good correlation with the porosities of the tablets.

Photoacoustic evaluation of elasticity and integrity of pharmaceutical tablets

A nondestructive method based on pulse photoacoustics was applied for evaluation of elasticity and integrity of pharmaceutical tablets. Variations in porosity, density and sodium chloride content of microcrystalline cellulose tablets were found to be related to parameters extracted from the through-transmitted ultrasonic wave forms. By using the amplitudes and ultrasonic velocities of these wave forms, it was possible to obtain values of a transverse to longitudinal amplitude ratio, and also elastic parameters, such as Youngs and shear moduli, for the tablets. Poissons ratio was calculated from the elastic moduli as well as from the amplitudes. An exponential relationship between tablet porosity and the attenuation of longitudinal wave form was noticed. The transverse to longitudinal amplitude ratio and the amplitudinal Poissons ratio were indicative of structural variations, e.g., changes in the porosity and the sodium chloride content of tablets. Youngs and shear moduli of microcrystalline cellulose tablets were found to follow similar porosity trends to those in previously published beam bending and twisting studies, although the absolute values and the values extrapolated to zero porosity were slightly smaller. The Poissons ratio calculated from the experimental Youngs and shear modulus values was also in agreement with earlier studies, but the values extrapolated to zero porosity differed significantly. The method is a promising tool for evaluating the elastic properties of tableting materials and the structural variations in tablets.