Abstract
Objective: The objective of the current study was to explore top down methods of size reduction like high speed homogenisation and media milling in synergism with spray drying in amorphization and solubility enhancement of BCS Class II antilipidemic drug Simvastatin USP.
 Methods: Spray-dried micronized simvastatin USP was formulated by homogenisation and media milling of drug suspension in optimized stabilizer solution. Stabilizer combination, duration of homogenisation and ball milling and drug: stabilizer ratio was optimized. The obtained dispersion was transformed into solid powder using spray drying. The obtained Spray-dried micronized Simvastatin USP was evaluated for visual morphology, Infrared spectroscopy, Differential scanning calorimetry, in vitro drug release studies, X-Ray diffractometry, Scanning electron microscopy, contact angle measurement, solubility studies, dispersibility studies and intrinsic dissolution rate testing.
 Results: Spray-dried micronized simvastatin USP was found to show amorphization of crystalline Simvastatin USP as confirmed by the absence of drug peak in Differential scanning calorimetry and lowered signal intensity in X-Ray diffraction studies. Spray-dried micronized Simvastatin USP was found to show enhanced drug hydrophilicity and solubility as confirmed by lowering in contact angle and increase in solubility and ease of dispersibility observations. In vitro dissolution testing and intrinsic dissolution rate testing were found to show an increase in drug release from 11% to 79% and 4 mg min-1 cm-2 to 17 mg min-1 cm-2 for drug and Spray-dried micronized Simvastatin USP respectively.
 Conclusion: Media milling in synergism with spray-drying was found to be a prospective solubility enhancement technique for poorly-soluble Simvastatin USP.
Highlights
Different active pharmaceutical ingredients discovered via high throughput screening or combinatorial chemistry have been attempted in designing of dosage form for oral administration as the oral route is very convenient in terms of patient administration of the dosage form [1, 2]
The contact angles of single and combination stabilizer solutions are as shown in fig. 2
The enhancement in size may be contributed to the initiation of aggregation phenomena owing to soft nature of Simvastatin USP and the relatively lesser amount of stabilizer
Summary
Different active pharmaceutical ingredients discovered via high throughput screening or combinatorial chemistry have been attempted in designing of dosage form for oral administration as the oral route is very convenient in terms of patient administration of the dosage form [1, 2]. The poor solubility characteristics of pharmacologically active lipophilic compounds greatly affect their bioavailability and pose a challenge to formulation scientists in designing suitable bioavailable dosage forms [3,4,5]. This issue is often seen for BCS Class II drugs exhibiting high permeability but poor solubility [6]. Pharmaceutical solids existing in amorphous form are high energy systems which exhibit higher solubility and faster dissolution velocities and are preferred over crystalline forms [8]. Different arrangements of lattice structure give rise to distinct crystalline forms of drugs exhibiting variable aqueous solubility. Modulations in drug crystalline characteristics can pave a way for modulations in solubility of the drug [9]
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