Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

Amorphous ternary solid dispersion has become one of the strategies commonly used for improving the solubility and bioavailability of poorly water soluble drugs. Such multicomponent solid dispersion can be obtained by different techniques, this chapter provides an overview of ternary solid dispersion by co-milling method from the perspectives of physico-chemical characteristics in vitro and in vivo performance. A considerable improvement of solubility was obtained for many active pharmaceutical ingredients (e.g., Ibuprofen, Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen) and this was correlated to the synergy of multiple factors (hydrophilicity enhancement, particle size reduction, drug-carrier interactions, anti-plasticizing effect and complexation efficiency). This enhanced pharmacokinetic properties and bioavailability of these drug molecules (1.49 to 15-folds increase in plasma drug concentration). A particular focus was accorded to compare the ternary and binary system including Ibuprofen and highlighting the contribution of thermal and spectral characterization techniques. The addition of polyvinylpyrrolidone (PVP K30), a low molecular weight molecule, into the binary solid dispersion (Ibuprofen/β-cyclodextrin), leads to a 1.5–2 folds increase in the drug intrinsic dissolution rate only after 10 min. This resulted from physical stabilization of amorphous Ibuprofen by reducing its molecular mobility and inhibiting its recristallization even under stress conditions (75% RH and T = 40°C for six months)

Multifunctional Roles of PVP as a Versatile Biomaterial in Solid State

Polyvinylpyrrolidone (PVP) has proven to be a highly versatile material, as evidenced by its long history as multifunctional biomaterial with a wide range of high-performance applications (e.g., tissue engineering, drug delivery systems, and ophthalmologic applications). PVP was frequently used in medical and pharmaceutical field due to its several interesting properties (higher glass transition temperature, water solubility, biocompatibility, biodegradability, chemical stability, very good adhesive, and emulsifying agent). This chapter highlights the multifunctional roles of PVP in pharmaceutical formulations in solid state. In fact, PVP acted as a stabilizing agent for various amorphous drug molecules by minimizing their molecular mobility. Physical stabilization resulted from the reinforcement of intermolecular interactions in binary or ternary systems due to the synergetic effect of PVP. This made it possible to overcome several challenges for drug formulations (e.g., solubility and bioavailability weakness, physical instability under stress conditions, complexation efficiency of cyclodextrin molecules). In this chapter, the effect of PVP on the binary solid dispersion (indomethacin:kaolin) is discussed. We have shown that PVP enhanced physical stability of amorphous indomethacin under stress conditions (at RH: 75% and T = 40°C for three months), leading to the improvement of drug aqueous solubility by suppressing kaolin adsorption effect

The persistence and crystallization behavior of atorvastatin calcium amorphous dispersions in polyvinylpyrrolidone

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Crystallization (or not) of active pharmaceutical ingredients in thin films

International audienceUtilizing surfaces for nucleation and growth is often adopted as a means to enhance crystallization. Certain surfaces can accelerate crystallization while other prevent it. On the other hand, constrains induced by the surface can trigger crystal growth on well-defined contact planes and thus along specific crystallographic directions i.e. texture or epitaxial growth can result. It has also been shown that surfaces can increase the crystallization rate when compared to the bulk. Furthermore, it has been shown for several organic semiconductors (organic molecules deposited on flat solid substrates as thin films, a hundred of nm thick) that new polymorphs could be stabilized only close to the substrate (called “substrate induced polymorphs or SSPs). In this presentation, we report two cases of thin film deposition of active pharmaceutical ingredients illustrating the ability of a solid surface and the confinement geometry to drastically change the crystallization outcome and therefore ultimately the properties of the drug product. The first example concerns pyrazinamide, an active pharmaceutical ingredient used in the treatment of tuberculosis, which possesses 4 polymorphic forms. Here, thin film deposition of pyrazinamide shows the long-time persistence of metastable polymorphs while the stable polymorph is never obtained. The second example pertains to ketoprofen (a non-steroidal anti-inflammatory) for which amorphous solid dispersions could be achieved upon thin film co-deposition with polyethylene oxide. It appears that these amorphous solid dispersions could be preserved for several months even when submitted to a high relative humidity atmosphere, depending on the film thickness

Fabrication of amorphous solid dispersions of ketoprofen by spin coating and assessment of their stability with relative humidity

International audienceUtilizing surfaces for nucleation and growth is often adopted as a means to enhance crystallization. Certain surfaces can accelerate crystallization while other prevent it. Moreover, constraints induced by the surface can trigger crystal growth on well-defined contact planes and thus along specific crystallographic directions i.e. texture or epitaxial growth can result. It has also been shown that surfaces can increase the crystallization rate when compared to the bulk. Furthermore, it has been shown for several organic semiconductors (organic molecules deposited on flat solid substrates as thin films a hundred of nm thick) that new polymorphs could be stabilized only close to the substrate (called “substrate induced polymorphs or SSPs). In this poster presentation, we report the use of thin film deposition by spin-coating on glass substrates to fabricate amorphous solid dispersions of ketoprofen (KTP, an non-steroidal anti-inflammatory) with polyethylene glycol (PEG) an inert polymer.Namely, KTP and PEG are solubilized in dichloromethane at different PEG mass content (from 0% to 100%) and different concentrations (10 mg/mL, 20 mg/mL and 40 mg/mL) and the solution is cast on a pre-cleaned glass substrates which is subsequently rotated at a given speed during a given time. All the films have been characterized by powder X-ray diffraction (PXRD) and atomic force microscopy (AFM). Furthermore, the different films were submitted to different wet atmospheres (0%, 57%, 84% and 98% of relative humidity –RH-) during several months and subsequently characterized by XRPD and AFM to assess their stability and find the sample parameters which influence this stability. In particular, solution concentration appears to significantly influence the stability of the amorphous dispersions

Crystallization of active pharmaceutical ingredients in thin films

International audienceUtilizing surfaces for nucleation and growth is often adopted as a means to enhance crystallization. Certain surfaces can accelerate crystallization while other prevent it. On the other hand, constrains induced by the surface can trigger crystal growth on well-defined contact planes and thus along specific crystallographic directions i.e. texture or epitaxial growth can result. It has also been shown that surfaces can increase the crystallization rate when compared to the bulk. Furthermore, it has been shown for several organic semiconductors (organic molecules deposited on flat solid substrates as thin films a hundred of nm thick) that new polymorphs could be stabilized only close to the substrate (called “substrate induced polymorphs or SSPs). In this presentation, we report two cases of crystallization of active pharmaceutical ingredients (APIs) showing the ability of a solid surface to drastically change the outcome of the crystallization and thus modify the properties of the API. The first example concerns pyrazinamide (PZA), an API used in the treatment of tuberculosis, which possesses 4 polymorphic forms. Here, thin film deposition of PZA alone or with an additive (dimethyl urea –DMU-) shows the long-time stabilization of a metastable polymorph. The second example pertains to ketoprofen (an non-steroidal anti-inflammatory) for which amorphous solid dispersions could be achieved upon thin film co-deposition with polyethylene oxide. Film thickness and relative humidity proved to significantly influence the stability of those amorphous solid dispersions

Crystallization of active pharmaceutical ingredients in thin films

International audienceUtilizing surfaces for nucleation and growth is often adopted as a means to enhance crystallization. Certain surfaces can accelerate crystallization while other prevent it. On the other hand, constrains induced by the surface can trigger crystal growth on well-defined contact planes and thus along specific crystallographic directions i.e. texture or epitaxial growth can result. It has also been shown that surfaces can increase the crystallization rate when compared to the bulk. Furthermore, it has been shown for several organic semiconductors (organic molecules deposited on flat solid substrates as thin films a hundred of nm thick) that new polymorphs could be stabilized only close to the substrate (called “substrate induced polymorphs or SSPs). In this presentation, we report two cases of crystallization of active pharmaceutical ingredients (APIs) showing the ability of a solid surface to drastically change the outcome of the crystallization and thus modify the properties of the API. The first example concerns pyrazinamide (PZA), an API used in the treatment of tuberculosis, which possesses 4 polymorphic forms. Here, thin film deposition of PZA alone or with an additive (dimethyl urea –DMU-) shows the long-time stabilization of a metastable polymorph. The second example pertains to ketoprofen (an non-steroidal anti-inflammatory) for which amorphous solid dispersions could be achieved upon thin film co-deposition with polyethylene oxide. Film thickness and relative humidity proved to significantly influence the stability of those amorphous solid dispersions

Does the trihydrate of atorvastatin calcium possess a melting point?

International audienceTo decide whether an active pharmaceutical ingredient can be used in its amorphous form in drug formulations, often the glass transition is studied in relation to the melting point of the pharmaceutical. If the glass transition temperature is high enough and found relatively close to the melting point, the pharmaceutical is considered to be a good glass former. However, it is obviously important that the observed melting point and glass transition involve exactly the same system, otherwise the two temperatures cannot be compared. Although this may seem trivial, in the case of hydrates, where water may leave the system on heating, the composition of the system may not be evident. Atorvastatin calcium is a case in point, where confusing terminology, absence of a proper an-hydrate form, and loss of water on heating lead to several doubtful conclusions in the literature. However, considering that no anhydrate crystal has ever been observed and that the glass transition of the anhydrous system is found at 144°C, it can be concluded that if the system is kept isolated from water, the chances that atorvastatin calcium crystallises at room temperature is negligible. The paper discusses the various thermal effects of atorvastatin calcium on heating and proposes a tentative binary phase diagram with water