In this paper, a novel approach to determine stable concentration in API-polymer systems is presented. As a model, binary amorphous mixtures flutamide (FL) drug with a copolymer Kollidon VA64 (PVP/VA) have been used. It is worthwhile to note that finding an effective method to achieve this goal is a matter of great importance because physical stability of the amorphous pharmaceuticals is the key issue that is investigated worldwide. Due to the fact that molecular dynamics was found to be the crucial factor affecting physical stability of disordered pharmaceuticals, we examined it for both neat FL and its PVP/VA mixtures by means of broadband dielectric spectroscopy (BDS). Thorough investigation of the impact of polymeric additive on the molecular mobility of disordered FL reveals unusual, previously unreported behavior. Namely, simultaneously with the beginning of the recrystallization process, we observe some transformation from unstable supersaturated concentration of investigated mixture to the different, unknown concentration of FL-PVP/VA. Observed, during BDS experiment, transformation enables us to determine the limiting, highly physically stable concentration of FL in PVP/VA polymer (saturated solution), which is equivalent to FL + 41% wt. of PVP/VA. The described high physical stability of this unveiled system has been confirmed by means of long-term XRD measurements. According to our knowledge, this is the first time when such a behavior has been observed by means of BDS.

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

In this article we thoroughly investigated the physical stability of the amorphous form of a chloramphenicol drug. The tendency toward recrystallization of this drug has been examined (i) at nonisothermal conditions by means of a DSC technique; (ii) at isothermal conditions and temperature close to T by means of dielectric spectroscopy; (iii) at isothermal conditions and elevated temperatures of T = 323 K and 338 K by dielectric spectroscopy; and (iv) at conditions imitating the manufacturing procedure (i.e., elevated temperature and compression procedure). Our investigations have shown that amorphous chloramphenicol, stored at both standard storage and elevated temperature conditions, does not reveal a tendency toward recrystallization. However, compression significantly changes this behavior and destabilizes the examined compound. We found that due to chemical equilibration of the sample, the elongation of the storage time before compression might improve the physical stability of the examined pharmaceutical exposed to compression 34-times.

Transformation of poorly water-soluble crystalline pharmaceuticals to the amorphous form is one of the most promising strategies to improve their oral bioavailability. Unfortunately, the amorphous drugs are usually thermodynamically unstable and may quickly return to their crystalline form. A very promising way to enhance the physical stability of amorphous drugs is to prepare amorphous compositions of APIs with certain excipients which can be characterized by significantly different molecular weights, such as polymers, acetate saccharides, and other APIs. By using different experimental techniques (broadband dielectric spectroscopy, differential scanning calorimetry, X-ray diffraction) we compare the effect of adding the large molecular weight polymer-polyvinylpyrrolidone (PVP K30)-and the small molecular weight excipient-octaacetylmaltose (acMAL)-on molecular dynamics as well as the tendency to recrystallization of the amorphous celecoxib (CEL) in the amorphous solid dispersions: CEL-PVP and CEL-acMAL. The physical stability investigations of the binary systems were performed in both the supercooled liquid and glassy states. We found that acMAL is a better inhibitor of recrystallization of amorphous CEL than PVP K30 deep in the glassy state (T < T). In contrast, PVP K30 is a better crystallization inhibitor of CEL than acMAL in the supercooled liquid state (at T > T). We discuss molecular factors governing the recrystallization of amorphous CEL in examined solid dispersions.

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2The pretransitional behavior of dodecylcyanobiphenyl (12CB, isotropic -smectic Asolid mesomorphism) with d=50nm BaTiO3 nanoparticles (NPs) linked to the cubic phase was monitored via temperature studies of dielectric constant. Tests were carried out in the isotropic, liquid crystal mesomorphic, and solid phases. For each phase transition the same value of the "critical" exponent ~ 0.5 was obtained, including nanocolloids. All phase transitions show the weakly discontinuous nature. The temperature metric of the discontinuity T notably decreases when adding nanoparticles. The addition of nanoparticles first decreases the dielectric constant by approximately 50 % in comparison with pure 12CB, but already for a concentration ~ x = 0.4 % NP an increase over 50 % takes place. It is notable that for the latter concentration unique hallmarks of the pretransitional effect emerge also for the solidmesophase transition. All these indicate the important impact of nanoparticles on multimolecular, mesoscale fluctuations.

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The self-assembly phenomenon of amphiphiles has attracted particular attention in recent years due to its wide range of applications. The formation of nanoassemblies able to solubilize sparingly water-soluble drugs was found to be a strategy to solve the problem of poor solubility of active pharmaceutical ingredients. Binary and ternary solid dispersions containing Biopharmaceutics Classification System (BCS) class II drug bicalutamide and either Poloxamer®188 or Poloxamer®407 as the surface active agents were obtained by either spray drying or solvent evaporation under reduced pressure. Both processes led to morphological changes and a reduction of particle size, as confirmed by scanning electron microscopy and laser diffraction measurements. The increase in powder wettability was confirmed by means of contact angle measurements. The effect of an alteration of the crystal structure was followed by powder X-ray diffractometry while thermal properties were determined using differential scanning calorimetry. Interestingly, bicalutamide exhibited a polymorph transition after spray drying with the poloxamer and polyvinylpyrrolidone (PVP), while the poloxamer underwent partial amorphization. Moreover, due to the surface activity of the carrier, the solid dispersions formed nanoaggregates in water, as confirmed using dynamic light scattering measurements. The aggregates measuring 200–300 nm in diameter were able to solubilize bicalutamide inside the hydrophobic inner parts. The self-assembly of binary systems was found to improve the amount of dissolved bicalutamide by 4- to 8-fold in comparison to untreated drug. The improvement in drug dissolution was correlated with the solubilization of poorly soluble molecules by macromolecules, as assessed using emission spectroscopy.