Effectiveness of Spray Congealing to Obtain Physically Stabilized Amorphous Dispersions of a Poorly Soluble Thermosensitive API

Abstract

Abstract. An amorphous phase produced by micronization up to the molecular or colloidal level of a poorly soluble drug having low lipophilicity can distinctly enhance its solubility characteristics. However, though dispersing the molten mass of a poorly water-soluble drug within polymeric matrix has been found to be most effective in formation of molecular dispersions, the drug molecules which melt at high temperature also accompanied by decomposition, such as acetazolamide, are difficult to formulate as molecular dispersions. Hence, a method is proposed to obtain molecular dispersions of acetazolamide with poloxamer-237 by spray congealing under optimal heat treatment. Uniform molecular and/or colloidal dispersions of the drug were achieved with instantaneous solvent evaporation by mixing a drug solution with molten mass of the plasticizer matrix. Immobilization of dispersed drug molecules was effected subsequently through rapid solidification by spray congealing. Initial characterization of 1:1, 1:1.5, and 1:2 ratios of solid dispersions and devitrification study of an optimized (1:2) ratio ensured efficacy of the proposed method in formation of physically stabilized amorphous systems without thermal degradation and hence resulted in more than ninefold rise in solubility and more than 90% dissolution within initial 10 min. With 1:2 ratio, molecular dispersions could be achieved by initial solvent evaporation stage, which when subjected to spray congealing produced physically stable amorphous systems, without signs of thermal degradation. This study also proposes an opportunity for selection of those polymers with which the drug is immiscible in their fluid state, yet obtaining molecular dispersions.

Spray Congealing: An Emerging Technology to Prepare Solid Dispersions with Enhanced Oral Bioavailability of Poorly Water Soluble Drugs

“…In the same study, the dissolution profiles were also affected by the drug amount, and in particular lower drug contents led to higher improvements in drug dissolution rate. The best dissolution performance was obtained by the SD with the highest percentage of poloxamer 237 [33]. However, poloxamers are known to have thermoreversible gelation properties; before poloxamer dissolution, formation of gel layer might occur in the highly concentrated polymer regions, at the particle-medium interface.…”

“…It detects changes in the solid state such as hydrogen bonding or π−π interactions which are reflected as peak shifts of functional groups [62]. For example, Kulthe et al [33] examined the drug polymer interactions between acetazolamide and poloxamer 237 in spray congealed MPs by means of FT-IR. A slight broadening and shift in the position of the free C = O vibration and N–H stretching vibration, characteristic peaks of the drug, to lower wavenumber suggested intermolecular hydrogen bonding in SD.…”

“…In this case, during cooling, the solubilized drug re-solidify in disordered clusters within the carrier matrix, with a complete or partial loss of the ordered crystalline structure. Reduced drug crystallinity has been reported for spray congealed MPs containing metronidazole [49] and diclofenac [88], whereas complete conversion into the amorphous form was observed for acetazolamide [33]. It is well-known that solids in the amorphous state have a higher solubility, as no energy is required to break up the crystal lattice in the dissolution process.…”

Effect of Lipid Additives and Drug on the Rheological Properties of Molten Paraffin Wax, Degree of Surface Drug Coating, and Drug Release in Spray-Congealed Microparticles

“…Drug release rates can be altered by a prudent choice of matrix materials [ 22 ], additives, and physical properties of the drug such as particle size and crystallinity [ 31 ]. Hydrophilic materials such as higher molecular weight polyethylene glycols [ 40 , 41 , 42 ], poloxamers [ 2 , 6 , 43 ] and gelucires [ 44 , 45 , 46 ] have been investigated as potential matrix materials to enhance the dissolution rates of poorly water-soluble drugs. On the contrary, by employing lipophilic materials such as carnauba wax [ 3 ], microcrystalline wax [ 34 ], hydrogenated vegetable oils [ 47 , 48 , 49 ], tristearin [ 50 ], stearic acid [ 22 , 51 , 52 ], glyceryl behenate [ 53 ] and glyceryl dibehenate [ 52 , 54 ], microparticles with sustained-release properties can be produced.…”