Physical properties and solubility studies of Nifedipine-PEG 1450/HPMCAS-HF solid dispersions.

Low-order high-energy nifedipine (NIF) solid dispersions (SDs) were generated by melt solvent amorphization with polyethylene glycol (PEG) 1450 and hypromellose acetate succinate (HPMCAS-HF) to increase NIF solubility while achieving acceptable physical stability. HPMCAS-HF was used as a crystallization inhibitor. Individual formulation components, their physical mixtures (PMs), and SDs were characterized by differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy (FTIR). NIF solubility and percent crystallinity (PC) were determined at the initial time and after 5 days stored at 25 °C and 60% RH. FTIR indicated that hydrogen bonding was involved with the amorphization process. FTIR showed that NIF:HPMCAS-HF intermolecular interactions were weaker than NIF:PEG 1450 interactions. NIF:PEG 1450 SD solubilities were significantly higher than their PM counterparts (p < 0.0001). The solubilities of NIF:PEG 1450:HPMCAS-HF SDs were significantly higher than their corresponding NIF:PEG 1450 SDs (p < 0.0001-0.043). All the SD solubilities showed a statistically significant decrease (p < 0.0001) after storage for 5 days. SDs PC were statistically lower than their comparable PMs (p < 0.0001). The PCs of SDs with HPMCAS-HF were significantly lower than SDs not containing only PEG 1450. All SDs exhibited a significant increase in PC (p < 0.0001-0.0089) on storage. Thermogravimetric analysis results showed that HPMCAS-HF bound water at higher temperatures than PEG 1450 (p < 0.0001-0.0039). HPMCAS-HF slowed the crystallization process of SDs, although it did not completely inhibit NIF crystal growth.

Computational Predictability of Microsponge Properties Using Different Multivariate Models.

The capabilities of principal component regression (PCR) and multiple linear regression (MLR) were evaluated to decipher and predict the impact of formulation and process parameters on the modeled metronidazole benzoate (MB)-ethyl cellulose (EC) microsponge (MBECM) properties. MBECM were prepared by a quasi-emulsion solvent diffusion method. A minimum experimentation was designed using Box-Behnken approach with one center point after initial screening experiments. Data was modeled by principal component analysis (PCA), PCR, and MLR. Two distinct groupings of developed MBECM was observed in initial qualitative PCA as a function of their respective formulation and processing parameters. Group A formulations with low dichloromethane, high PVA, and low stirring speed exhibited larger particle size, lower entrapment efficiency (EE), and lower actual drug content (ADC) than Group B formulations. Optimized quantitative PCR and MLR models demonstrated a linear dependence of particle size and quadratic dependence of EE and ADC on the studied formulation and process parameters. Interestingly, MLR models showed relatively better predictability of the selected MBECM formulation properties when compared with PCR. MBECM were amorphous in nature and spherical shaped. Carbopol® 940 NF based hydrogel of selected MBECM formulation exhibited a prolonged MB release than the commercial MB gel (Metrogyl®), showing no signs of necrosis in the goat mucosa. Thus, a properly designed minimum experimentation coupled with multivariate modeling generated a knowledge-rich target space, which enabled to understand and predict the performance of developed MBECM within a prescribed design space.

Factorial Design Based Multivariate Modeling and Optimization of Tunable Bioresponsive Arginine Grafted Poly(cystaminebis(acrylamide)-diaminohexane) Polymeric Matrix Based Nanocarriers.

Desired characteristics of nanocarriers are crucial to explore its therapeutic potential. This investigation aimed to develop tunable bioresponsive newly synthesized unique arginine grafted poly(cystaminebis(acrylamide)-diaminohexane) [ABP] polymeric matrix based nanocarriers by using L9 Taguchi factorial design, desirability function, and multivariate method. The selected formulation and process parameters were ABP concentration, acetone concentration, the volume ratio of acetone to ABP solution, and drug concentration. The measured nanocarrier characteristics were particle size, polydispersity index, zeta potential, and percentage drug loading. Experimental validation of nanocarrier characteristics computed from initially developed predictive model showed nonsignificant differences (p > 0.05). The multivariate modeling based optimized cationic nanocarrier formulation of <100 nm loaded with hydrophilic acetaminophen was readapted for a hydrophobic etoposide loading without significant changes (p > 0.05) except for improved loading percentage. This is the first study focusing on ABP polymeric matrix based nanocarrier development. Nanocarrier particle size was stable in PBS 7.4 for 48 h. The increase of zeta potential at lower pH 6.4, compared to the physiological pH, showed possible endosomal escape capability. The glutathione triggered release at the physiological conditions indicated the competence of cytosolic targeting delivery of the loaded drug from bioresponsive nanocarriers. In conclusion, this unique systematic approach provides rational evaluation and prediction of a tunable bioresponsive ABP based matrix nanocarrier, which was built on selected limited number of smart experimentation.

Comparative binder efficiency modeling of dry granulation binders using roller compaction.

Roller compaction parameters' impact on granules and tableting properties of coprocessed Avicel® DG [ADG], a physical mixture of the two components at the same composition present in ADG [PADCP], and microcrystalline cellulose and Kollidon® VA-64 Fine physical mixture [KVA64] was quantified by analysis of variance (ANOVA) and multivariate methods. Roller force, roller gap, and roller speed levels were selected for evaluation. A 33 full-factorial experimental design with three center points for roller force, roller gap, and roller speed was used. The response parameters studied were granule-to-fines (GF) ratio, compressibility index (CI), tablet thickness (TT), tablet friability (TF), tablet breaking force (TBF) and disintegration time (DT). A model acetaminophen tablet formulation was roller granulated and tableted at 10 kg scale. Principal component analysis of ADG and PADCP formulations were separated from KVA64 formulations, indicating different granule and tableting properties were binder dependent. This difference in binder performance was also confirmed by ANOVA. The ANOVA also showed that there were no statistical performance differences between coprocessed ADG and its comparable physical blend with the exception of TT. Principal component regression (PCR) analyses of ADG and PADCP revealed that these excipients exhibited a statistically significant negative effect on granules-to-fine (GF) ratio, TT, TBF, and DT. KVA64 demonstrated a positive effect on these parameters. The KVA64 physical mixture demonstrated an overall better performance and binding capability. This study strongly suggests that there is no performance advantage of coprocessed Avicel® DG when compared to a physical mixture of the two components at the same composition.

Physico-Mechanical Properties of Coprocessed Excipient MicroceLac® 100 by DM(3) Approach.

PURPOSE: To determine the effect of relative humidity (RH) and hydroxypropyl methylcellulose (HPMC) on the physico-mechanical properties of coprocessed MacroceLac(®) 100 using 'DM(3)' approach. METHODS: Effects of RH and 5% w/w HPMC on MacroceLac(®) 100 Compressibility Index (CI) and tablet mechanical strength (TMS) were evaluated by 'DM(3)'. The 'DM(3)' approach evaluates material properties by combining 'design of experiments', material's 'macroscopic' properties, 'molecular' properties, and 'multivariate analysis' tools. A 4X4 full-factorial experimental design was used to study the relationship of MacroceLac(®) 100 molecular properties (moisture content, dehydration, crystallization, fusion enthalpy, and moisture uptake) and macroscopic particle size and shape on CI and TMS. A physical binary mixture (PBM) of similar composition to MacroceLac(®) 100 was also evaluated. Multivariate analysis of variance (MANOVA), principle component analysis, and partial least squares (PLS) were used to analyze the data. RESULTS: MANOVA CI ranking was: PBM-HPMC > PBM > MicroceLac(®)100 > MicroceLac(®)100-HPMC (p < 0.0001). MANOVA showed PBM's and PBM-HPMC's TMS values were lower than MicroceLac(®)100 and MicroceLac(®)100-HPMC (p < 0.0001). PLS showed that % RH, HPMC, and several molecular properties significantly affected CI and TMS. CONCLUSIONS: Significant MicroceLac(®)100 changes occurred with % RH exposure affecting performance attributes. HPMC physical addition did not prevent molecular or macroscopic matrix changes.

Characterization of critical physical and mechanical properties of freeze-dried grape powder for development of a clinical patient delivery system.

Grapes are hypothesized to be a "food medicine." Freeze-dried grape powder (FDGP) is being used to test clinical activity for a variety of applications and a reproducible and reliable delivery system was required. The FDGP was characterized using traditional physico-chemical methods to generate the data needed to identify its primary liability, i.e. moisture sorption. Above a threshold level of moisture content (~25% w/w, at RT), the material becomes both difficult to handle and exhibits significant degradation of several potentially clinically important chemical components (catechin, epicatechin, resveratrol). A moisture sorption isotherm was then used to tie the threshold to the exposure relative humidity above which this occurs. Kinetic uptake studies were used to estimate the maximum safe exposure time at a given humidity (a square root time dependence of moisture uptake was observed). Armed with this knowledge, a FDGP compact coated with a compression coat [100% bees wax or combinations of carnauba wax (70%) with HPC (30%) or Avicel(®) PH 102 (30%) or lactose monohydrate (30%)] was developed that will insure the shelf life of the material without the need for special handling for approximately more than 3 months.

Comparative evaluation of the powder and compression properties of various grades and brands of microcrystalline cellulose by multivariate methods.

The present work challenges a newly developed approach to tablet formulation development by using chemically identical materials (grades and brands of microcrystalline cellulose). Tablet properties with respect to process and formulation parameters (e.g. compression speed, added lubricant and Emcompress fractions) were evaluated by 2(3)-factorial designs. Tablets of constant true volume were prepared on a compaction simulator at constant pressure (approx. 100 MPa). The highly repeatable and accurate force-displacement data obtained was evaluated by simple 'in-die' Heckel method and work descriptors. Relationships and interactions between formulation, process and tablet parameters were identified and quantified by multivariate analysis techniques; principal component analysis (PCA) and partial least square regressions (PLS). The method proved to be able to distinguish between different grades of MCC and even between two different brands of the same grade (Avicel PH 101 and Vivapur 101). One example of interaction was studied in more detail by mixed level design: The interaction effect of lubricant and Emcompress on elastic recovery of Avicel PH 102 was demonstrated to be complex and non-linear using the development tool under investigation.