Assessing the Interrelationship of Microstructure, Properties, Drug Release Performance, and Preparation Process for Amorphous Solid Dispersions Via Noninvasive Imaging Analytics and Material Characterization.

PURPOSE: The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution performance for amorphous solid dispersions (ASDs) prepared using different methods. METHODS: ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional quantification and understanding of the drug product intermediates and tablets. RESULTS: Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in microstructure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders. XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong correlation with micro dissolution data. CONCLUSION: Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship.

Investigation of Quantitative X-ray Microscopy for Assessment of API and Excipient Microstructure Evolution in Solid Dosage Processing.

Assessment and understanding of changes in particle size of active pharmaceutical ingredients (API) and excipients as a function of solid dosage form processing is an important but under-investigated area that can impact drug product quality. In this study, X-ray microscopy (XRM) was investigated as a method for determining the in situ particle size distribution of API agglomerates and an excipient at different processing stages in tablet manufacturing. An artificial intelligence (AI)-facilitated XRM image analysis tool was applied for quantitative analysis of thousands of individual particles, both of the API and the major filler component of the formulation, microcrystalline cellulose (MCC). Domain size distributions for API and MCC were generated along with the calculation of the porosity of each respective component. The API domain size distributions correlated with laser diffraction measurements and sieve analysis of the API, formulation blend, and granulation. The XRM analysis demonstrated that attrition of the API agglomerates occurred secondary to the granulation stage. These results were corroborated by particle size distribution and sieve potency data which showed generation of an API fines fraction. Additionally, changes in the XRM-calculated size distribution of MCC particles in subsequent processing steps were rationalized based on the known plastic deformation mechanism of MCC. The XRM data indicated that size distribution of the primary MCC particles, which make up the larger functional MCC agglomerates, is conserved across the stages of processing. The results indicate that XRM can be successfully applied as a direct, non-invasive method to track API and excipient particle properties and microstructure for in-process control samples and in the final solid dosage form. The XRM and AI image analysis methodology provides a data-rich way to interrogate the impact of processing stresses on API and excipients for enhanced process understanding and utilization for Quality by Design (QbD).

Feasibility of Focused Beam Reflectance Measurement (FBRM) for Analysis of Pharmaceutical Suspensions in Preclinical Development.

This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60 h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions.

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale.

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1 kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. < 1 mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.

Application of an Artificial Stomach-Duodenum Reduced Gastric pH Dog Model for Formulation Principle Assessment and Mechanistic Performance Understanding.

The objective of this study was to develop an artificial stomach-duodenum (ASD) dissolution model as an in vitro evaluation tool that would simulate the gastrointestinal physiology of gastric pH-reduced dogs as a method to assess formulations for a poorly soluble free acid compound with ng/mL solubility. After establishing the ASD model with well-controlled duodenum pH, 5 formulations each applying different solubilization principles were developed and their performance in the ASD model and in vivo in dogs was evaluated. Excellent correlations were obtained between dog area under the curve (AUC) and ASD AUC of 5 formulations evaluated with simulated intestinal fluid (r2 = 0.987) and fasted-state simulated intestinal fluid (r2 = 0.989) as the duodenum dissolution medium, indicating that the approach of infusing NaOH into duodenum compartment to maintain duodenum pH of an ASD worked properly in simulating gastric pH-reduced dog. Raman spectroscopy was used to study drug dissolution kinetics associated with different solubilization principles and the results suggested that the solubilization principles performed as designed. Spectroscopic results also identified that the compound formed a gel during dissolution and hypromellose maintained the drug-gelled state to avoid further solid form conversion. The implication of the compound physical gelation to drug dissolution kinetics and in vivo exposure are discussed.

Quantifying crystal form content in physical mixtures of (+/-)-tartaric acid and (+)-tartaric acid using near infrared reflectance spectroscopy.

The objective of this study was to use diffuse reflectance near infrared spectroscopy (NIRS) to determine racemic compound content in physical mixtures composed primarily of the enantiomorph and to assess the error, instrument reproducibility and limits of detection (LOD) and quantification (LOQ) of the method. Physical mixtures ranging from 0 to 25% (+/-)-tartaric acid in (+)-tartaric acid were prepared and spectra of the powder samples contained in glass vials were obtained using a Foss NIRSystems Model 5000 monochrometer equipped with a Rapid Content Analyzer scanning from 1100 to 2500 nm. A calibration curve was constructed by plotting (+/-)-tartaric acid weight percent against the 2(nd) derivative values of log (1/R) vs lambda at a single wavelength, normalized with a denominator wavelength (1480 nm/1280 nm). Excellent linearity was observed (R(2)=0.9999). The standard error of calibration (SEC) was 0.07 and the standard error of prediction (SEP) for the validation set was 0.11. Instrument and method errors for samples in the 2% composition range ((+/-)-tartaric acid in (+)-tartaric acid) were less than 1% RSD and 3% RSD, respectively. The practical LOD and LOQ were 0.1% and 0.5%, respectively, and comparable to the calculated LOD and LOQ. These studies show that NIRS can be used as a rapid and sensitive quantitative method for determining racemate content in the presence of the enatiomerically pure crystal in the solid-state.

Assessment of Pharmaceutical Powder Flowability using Shear Cell-Based Methods and Application of Jenike's Methodology.

Jenike's approach to hopper design for a large-scale (3150 L) conical hopper was applied to pharmaceutical powders to evaluate flow issues, such as funnel flow or cohesive arching. Seven grades of microcrystalline cellulose (MCC) and six powder blends were tested. A Schulze Ring Shear Tester measured the flow function, wall friction (using stainless steel coupons with a #2B or #8 finish) and compressibility. Hopper Index (HI, maximum hopper angle required for mass flow) and Arching Index (AI, minimum hopper outlet size to prevent cohesive arch formation) were computed using Mathcad(©) . For MCC, a linear relationship was observed between median particle size and the Jenike flow function coefficient. A curvilinear relationship was observed for powder blends indicating more complex flow behavior than based on median particle size alone. Powder bulk density had a minimal effect on AI for MCC grades. Overestimation of AI can occur with this method for pharmaceutical powders because the true shape of the flow function is not defined at very low consolidation pressures and linear extrapolation becomes unrepresentative. This instrumental limitation underscores the need for a precise and accurate test method to determine powder flow functions at very low levels of consolidation stress for pharmaceutical applications.

Assessment of crystallinity in processed sucrose by near-infrared spectroscopy and application to lyophiles.

The objective of this study was to investigate the capability of near-infrared spectroscopy (NIRS) to determine crystallinity in processed sucrose using a common set of calibration standards derived from binary physical mixtures. NIRS was applied as a primary method using binary mixtures of amorphous and crystalline standards to predict crystallinity in sucrose that was either rendered partially amorphous by milling, partially recrystallized from the amorphous phase, or amorphous lyophiles annealed to induce recrystallization. Crystallinity prediction in the case of milled crystalline and recrystallized amorphous sucrose was feasible using the two-state binary calibration mixtures applying a univariate model. NIRS results for milled sucrose were comparable to those obtained using X-ray powder diffraction. The changes in crystallinity after milling and recrystallization showed expected trends. However, the same NIRS univariate calibration method could not be successfully applied for directly through the vial. To overcome this complication, NIRS was applied as a secondary method relative to water vapor sorption (WVS) where a set of processed samples were measured using both NIRS and WVS and a partial least-squares model applied. The NIRS secondary method was successfully applied and provided a standard error of calibration of 2.11% and standard error of prediction of 3.76%.

Manipulating hydrate formation during high shear wet granulation using polymeric excipients.

Active pharmaceutical ingredients (API) can undergo an anhydrate to hydrate transformation during wet granulation and this transformation may either result in mixed crystalline forms or an unwanted form in the final drug product. Previous studies have shown that it may be possible to inhibit this transformation with polymeric excipients. In this study, three model compounds, caffeine (CAF), carbamazepine (CBZ), and sulfaguanidine (SGN), were subjected to high shear wet granulation and phase transformations were monitored using in-line Raman spectroscopy. Wet granulation was performed in the presence and absence of various polymeric excipients to determine the extent of the inhibitory effects. Although several polymers had some retardation effect, cross-linked poly(acrylic) acid was found to completely inhibit the CAF transformation and both hydroxypropyl methylcellulose and cross-linked poly(acrylic) acid completely inhibited the CBZ transformation. For SGN, transformation to the hydrate was rapid, even in the presence of the polymers. The observed inhibitory effects were attributed to either specific interactions between the polymer and the API crystal or substantial water absorption by the polymer. There was also evidence from physical property testing that the inclusion of a small amount of inhibitory polymer did not significantly change the compaction or flow behavior of the final granulation.

Influence of polymeric excipients on crystal hydrate formation kinetics in aqueous slurries.

Crystalline anhydrous active pharmaceutical ingredients (APIs) can potentially transform to the hydrate form during manufacturing processes involving water. The ability to understand and manipulate these transformations is important to maintain control of the solid state form of the API. The influence of various polymeric excipients on the anhydrate to hydrate transformation of caffeine, carbamazepine, and sulfaguanidine was investigated in this study. The transformation of the APIs in aqueous slurries was monitored using in-line Raman measurements and the resultant kinetic profiles provided insight into the inhibitory ability of the polymers investigated. The results showed that cross-linked poly(acrylic acid) inhibited the caffeine transformation and hydroxypropyl methylcellulose inhibited the carbamazepine transformation. None of the polymers tested were able to inhibit the sulfaguanidine transformation although some polymers were able to reduce the rate of the transformation with poly(vinylpyrrolidone) showing the greatest effect. It was found that the inhibitory polymers were able to either reduce crystal growth rates and/or increase the induction time preceding the nucleation event.

(+-)-Tartaric acid.

(+-)-Tartaric acid, C(4)H(6)O(6), crystallized from ethanol in space group P 1 macro. The structure is characterized by five hydrogen bonds, including the formation of a centrosymmetric carboxylic acid dimer which forms infinite chains along the body diagonal. These chains form sheets via hydrogen bonding between alpha-hydroxyl groups. The sheets are connected through a bifurcated hydrogen bond. Structural comparisons are made with homochiral (2R,3R)-(+)-tartaric acid.