A Simultaneous Differential Scanning Calorimetry-X-ray Diffraction Study of Olanzapine Crystallization from Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des.2019,19, 2751-2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.

The Development of Quasi-isothermal Calorimetry for the Measurement of Drug-Polymer Miscibility and Crystallization Kinetics: Olanzapine-Loaded PLGA Microparticles.

The assessment of drug-polymer equilibrium solubility is of critical importance for predicting suitable loading and physical stability of solid dispersion formulations. However, quantitative measurement of this parameter is nontrivial due to the difficulties associated with ascertaining equilibrium values in systems that are prone to supersaturation and are simultaneously highly viscous, thereby slowing the equilibration process considerably; no standard methodology has yet been agreed for such measurements. In this study, we propose a new approach involving quasi-isothermal modulated temperature DSC (QiMTDSC), whereby unsaturated and supersaturated samples are held at defined temperatures and subject to a sinusoidal heating signal at a zero underpinning heating rate, thereby allowing the heat capacity of the sample to be measured as a function of time and temperature. We are not only able to ascertain whether equilibrium has been reached by monitoring the time-dependent heat capacity signal, but we can also measure solubility as a function of temperature via the absolute heat capacity values of the components. We are also able to measure the kinetics of recrystallization from the supersaturated systems. Dispersions of olanzapine in PLGA at concentrations up to 50% w/w, prepared by spray drying, were prepared and characterized using conventional and QiMTDSC as well as hot stage microscopy. The new QiMTDSC protocol was successfully able to determine olanzapine solubility in PLGA at 90 °C to be 23.1 ± 6.1% w/w, which was comparable to the values calculated using other established methods at this temperature, while a temperature/solubility profile was obtained using the method at a range of temperatures. Drug crystallization kinetics from the solid dispersions could also be modeled directly from the QiMTDSC data using the Avrami approach, thereby allowing the effect of drug loading on the rate of crystallization and the effective completion of crystallization to be investigated. Overall, an alternative protocol for measuring drug-polymer solubility has been developed and validated via comparison to established methods, the approach allowing solubility as a function of temperature, identification of equilibrium following demixing, and kinetic analysis of crystallization to be performed within one set of experiments.

Water-based 3D inkjet printing of an oral pharmaceutical dosage form.

Inkjet printing is a form of additive manufacturing where liquid droplets are selectively deposited onto a substrate followed by solidification. The process provides significant potential advantages for producing solid oral dosage forms or tablets, including a reduction in the number of manufacturing steps as well as the ability to tailor a unique dosage regime to an individual patient. This study utilises solvent inkjet printing to print tablets through the use of a Fujifilm Dimatix printer. Using polyvinylpyrrolidone and thiamine hydrochloride (a model excipient and drug, respectively), a water-based ink formulation was developed to exhibit reliable and effective jetting properties. Tablets were printed on polyethylene terephthalate films where solvent evaporation in the ambient environment was the solidification mechanism. The tablets were shown to contain a drug loading commensurate with the composition of the ink, in its preferred polymorphic phase of a non-stoichiometric hydrate distributed homogenously. The printed tablets displayed rapid drug release. This paper illustrates solvent inkjet printing's ability to print entire free-standing tablets without an edible substrate being part of the tablet and the use of additional printing methods. Common problems with solvent-based inkjet printing, such as the use toxic solvents, are avoided. The strategy developed here for tablet manufacturing from a suitable ink is general and provides a framework for the formulation for any drug that is soluble in water.