Solid dispersions amorphous precipitations

Trigonal crystalline solid or amorphous powder mineral millerite has a yellow metallic luster color varies from yellow to brownish black density 5.30 to 6.65 g/cm3 exhibits three allotropic modifications (1) the acid-soluble amorphous alpha form obtained from nickel salt solution by precipitation with ammonium sulfide, (2) the alpha form rapidly transforms to a crystalline beta form as a brown colloidal dispersion upon exposure to air, and (3) a rhombo-hedral gamma modification found native as mineral millerite, which also can be prepared artificially under certain conditions. 

Chiou and Riegelman classified solid dispersions intothe following six representative types 1) simple eutectic mixtures 2) solid solutions 3) glass solutions and glass suspensions 4) amorphous precipitations in a crystalline carrier 5) compound or complex formation and 6) combinations of the previous five types. 

This type of solid dispersion is distinguished from a simple eutectic mixture by the fact that the drug is precipitated out in an amorphous form. In a simple eutectic mixture, the drug is precipitated out in a crystalline form. An example of this is the precipitation of sulfathiazole in the amorphous form in crystalline urea. It is postulated that a drug with a propensity to supercooling has more tendency to solidify as an amorphous form in the presence of a carrier. 

Chauhan H, Hui-Gu C, Atef E (2013) Correlating the behavior of polymers in solution as precipitation inhibitor to its amorphous stabilization ability in solid dispersions. J Pharm Sci 102(6) 1924-1935... 

Dong Z, Chatteqi A et al (2008) Eveiluation of solid state properties of solid dispersions prepeired by hot-melt extrusion and solvent co-precipitation. Int J Pharm 355(1-2) 141-149 Fakes MG, VakkalagaddaBJ et al (2009) Enhemcement of oral bioavailability of an HlV-attachment inhibitor by nanosizing and amorphous formulation approaches. Int J Pharm 370 167-174 Feng J, Xu L et al (2012) Evaluation of polymer carriers with regard to the bioavailability enhancement of bifendate solid dispersions prepared by hot-melt extrusion. Drug Dev Ind Pharm 38(6) 735-743... 

If a crystallization-inhibitory polymer is incorporated into the amorphous solid dispersion, the in vivo precipitation may be delayed or completely eliminated, resulting in much improved oral absorption. It is ideal if the polymeric carrier can function as a precipitation (crystallization) inhibitor during in vivo dissolution (Zhang et al. 2009). 

Yamashita et al. (2003) investigated the dissolution in acidic medium of solid dispersions containing the macrolide lactone tacrolimus in an amorphous state comparing three different polymers (HPMC, PVP, and PEG 6000) as the carrier. Rapid dissolution and supersaturated concentrations of tacrolimus up to 25-fold higher than the equilibrium solubility (2 mg/mL) were observed. Even though the polymer choice did not affect the maximum degree of supersaturation, it was only HPMC that could fully inhibit precipitation for up to 24 h. 

Dissolution of the salt of an acidic compound has its own complications. The salt is likely to convert to the free acid. When this happens, the liberated free acid may coat the surface of the remaining drug particles or nucleate on other particle surfaces, leading to a slowdown of dissolution (Wei-Qin 2(X)9). As described in the earlier sections, weak acids may rapidly precipitate/crystallize or gel in stomach before transit to the lower GI. It is therefore important to select amorphous solid dispersion and downstream technology, yielding a drug product with optimal supersaturation at physiologically relevant pH for absorption. 

Konno H, Taylor LS (2008) Abdity of different polymers to inhibit the crystallization of amorphous felodipine in the presence of moisture. Pharm Res 25 969-978 Konno H, Handa T, Alonzo DE, Taylor LS (2008) Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm 70 493 99 Kostewicz ES, Wunderlich M, Brauns U, Becker R, Bock T, Dressman JB (2(X)4) Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol 56 43-51... 

Amorphous material has higher apparent solubility and can remain in supersaturated state upon transit from gastric compartment to the intestinal compartment with or without the assistance of precipitation inhibitors. According to the model of API in polymer solubility (Marsac et al. 2006b), APIs have the tendency to crystallize to the more thermodynamically stable form. Inhibition of API crystallization in solid dispersion is attributed predominantly to kinetic stabilization (Marsac et al. 2006b). 

Abstract Supercritical antisolvent technology can precipitate polyvinylpyrrolidone (PVP) particles and crystallize paracetamol (PCM) crystals first separately and then together in the form of a solid dispersion. Supercritical carbon dioxide (SCCO2) is used as an antisolvent. For PVP particle generation, ethanol, acetone, and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 and 5 wt%, the operation pressure between 10 and 30 MPa, and the composition of ethanol/acetone solvent mixtures between 100 and 0 wt% of ethanol at a constant temperature of 313 K. An increase in the content of the poor solvent acetone in the initial solution leads to a significant decrease in mean particle size. Fully amorphous PVP powder always precipitates for all the parameters investigated. 

Generating PCM in an amorphous state was neither able by varying the process conditions nor the type of solvent. This follows the proposed criterion of ideal and nonideal solutes and that a switch between precipitation and crystallization is not possible by just changing the process parameters. Therefore, producing PCM in an amorphous state was realized by generating solid dispersions of PVP and the API at different polymer to API ratios. 

Solubility (in the molecular sense, rather than in the sense of forming dispersions and sols) opens up a number of possibilities. The first and perhaps most important, is that it allows size-selective precipitation [10], permitting monodisperse nanoparticles to be prepared. It is only when particles are monodisperse that their size-dependent physical properties can be studied in detail [6j. It is also possible to organize these monodisperse nanoparticles via slow evaporation to yield superlattices [11-13]. Superlattices of nanocrystals can rightly be described as a new class of materials, comprising crystals of crystals as opposed to most crystalline solids which are crystals of atoms [14]. In contrast, naturally occurring opals are crystals of amorphous silica spheres [15]. 

Based on phase-separation mechanisms, coacervation systems can be classified into two general types simple coacervation and complex coacervation. When only one polymer is involved, the process is referred to as simple coacervation, and when two or more polymers with opposite charges are involved, it is referred to as complex coacervation. In both cases, the coacervation takes place just before precipitation from solution. This separated phase in the form of amorphous, liquid droplets constituted the coacervate which is the polymer-rich solution. Deposition of this coacervate around the individual insoluble oil droplets or solid particles dispersed in the equilibrium liquid forms the embryonic capsules, and subsequent gelling of the deposited coacervate results in microcapsules. 

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