A method for the tribological assessment of oral pharmaceutical liquids.

OBJECTIVE: Patient acceptance of pediatric formulations is critical to compliance and consequently therapeutic outcomes; thus, having an in vitro method to evaluate sensory perception of pharmaceutical products would be beneficial. The objective of this research is to develop a sensitive and reproducible tribological method to characterize pharmaceutical suspensions at low force and sliding speeds. METHODS: The discriminating potential of the method was examined using tribology profiles (coefficient of friction (COF) vs. sliding speed) for commercially available products and products made for this study with widely varying sweetness, thickness, and grittiness; these formulations were used to judge the sensitivity of the method. Samples were measured using 3M Transpore™ surgical tape to simulate the tongue surface, steel half ring geometry, constant gap setting, target axial force of 2 N in a 600 s exponential ramp for rotation speed. RESULTS: The COF ranged from 0.1 to 0.6. For the speeds studied, the high viscosity commercial suspension ibuprofen drops and acetaminophen suspension show a classic Stribeck curve with an increasing COF at the higher rotation speeds, which indicates these formulations entered the hydrodynamic lubrication phase, while the lower viscosity suspensions only reached the mixed lubrication phase. CONCLUSION: The contribution of particles affects the COF in a dynamic tribologic pattern compared to products that are categorized as either low gritty or high viscosity. These results are important as they provide a potentially rapid in vitro method for screening pediatric medications and help to identify the factors that affect the palatability of pediatric formulations.

Development and Validation of Sample Preparation and an HPLC Analytical Method for Dissolution Testing in Fed-State Simulated Gastric Fluid-Illustrating Its Application for Ibuprofen and Ketoconazole Immediate Release Tablets.

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.

Evaluation of Abuse-Deterrent Characteristics of Tablets Prepared via Hot-Melt Extrusion.

In this study, the effect of formulation variables and process parameters on the abuse-deterrent (AD) characteristics of a matrix tablet manufactured using hot-melt extrusion (HME) was investigated. The formulation variables included polyethylene oxide (PEO) grades and its input level, while the HME process parameters varied were barrel temperature profile and die diameter. Depending on the diameter of the extrudate (2.5 mm or 5.0 mm), two different downstream processes were used to prepare the tablets: cryo-milling followed by compression for the 2.5 mm extrudate, and cutting followed by compression for the 5.0 mm extrudate. A D-optimal statistical design was used to evaluate the impact of formulation and process parameters on various responses, including tablet physical strength, particle size after manipulation, syringeability and injectability, solution viscosity, extractability in solvents, and dissolution rates. It was found that the post-HME extrusion processing method played a critical role in affecting the AD characteristics of abuse-deterrent formulations, likely through changing the tablet compactability and porosity. When the extrudates were cryo-milled-compressed, the tablets could be readily manipulated by milling, which led to high degree of extractability. Under high alcohol concentration, burst drug release was observed for the tablets compressed from cryo-milled extrudates. Additionally, heat exposure during HME process caused significant drop in PEO solution viscosity, likely due to thermal degradation.

Application of Optical Coherence Tomography Freeze-Drying Microscopy for Designing Lyophilization Process and Its Impact on Process Efficiency and Product Quality.

Optical coherence tomography freeze-drying microscopy (OCT-FDM) is a novel technique that allows the three-dimensional imaging of a drug product during the entire lyophilization process. OCT-FDM consists of a single-vial freeze dryer (SVFD) affixed with an optical coherence tomography (OCT) imaging system. Unlike the conventional techniques, such as modulated differential scanning calorimetry (mDSC) and light transmission freeze-drying microscopy, used for predicting the product collapse temperature (Tc), the OCT-FDM approach seeks to mimic the actual product and process conditions during the lyophilization process. However, there is limited understanding on the application of this emerging technique to the design of the lyophilization process. In this study, we investigated the suitability of OCT-FDM technique in designing a lyophilization process. Moreover, we compared the product quality attributes of the resulting lyophilized product manufactured using Tc, a critical process control parameter, as determined by OCT-FDM versus as estimated by mDSC. OCT-FDM analysis revealed the absence of collapse even for the low protein concentration (5 mg/ml) and low solid content formulation (1%w/v) studied. This was confirmed by lab scale lyophilization. In addition, lyophilization cycles designed using Tc values obtained from OCT-FDM were more efficient with higher sublimation rate and mass flux than the conventional cycles, since drying was conducted at higher shelf temperature. Finally, the quality attributes of the products lyophilized using Tc determined by OCT-FDM and mDSC were similar, and product shrinkage and cracks were observed in all the batches of freeze-dried products irrespective of the technique employed in predicting Tc.

Application of NIR chemometric methods for quantification of the crystalline fraction of warfarin sodium in drug product.

Monitoring of the physical state of warfarin sodium (WS) in products is essential for minimizing product quality variability in order to ensure consistent clinical performance. This study reports the development of chemometric models for quantifying the crystalline and amorphous fractions of WS in commercial drug products using NIR spectroscopy. Formulations based on commercially available products with different API to excipient ratio were used for the study. For each content, two formulations containing either lactose monohydrate or lactose anhydrous as the predominant formulation excipient were prepared. Two formulations containing either 100% amorphous WS (AWS) or crystalline WS (CWS) were prepared and mixed in various ratios to obtain sample matrices containing AWS/CWS 0-100%. The uniformity of the samples was confirmed by near infrared chemical imaging. Data were mathematically pretreated by multiplicative signal correction and Savitzky-Golay second derivative. Principal component regression and partial least square regression models were developed from mathematically treated data. All the models showed linear trend for amorphous and crystalline fractions of the WS as indicated by correlation and R(2) > 0.99 and >0.98, respectively. The models demonstrated good performance parameters with a low-root mean squared error, standard error and bias. The model predicted CWS and AWS contents were in very close agreement with the actual values. The study indicated the utility of NIR chemometric methods in quantification of the crystalline and/or amorphous fraction of WS in its products.

Application of chemometric methods to differential scanning calorimeter (DSC) to estimate nimodipine polymorphs from cosolvent system.

The focus of this study was to evaluate the applicability of chemometrics to differential scanning calorimetry data (DSC) to evaluate nimodipine polymorphs. Multivariate calibration models were built using DSC data from known mixtures of the nimodipine modification. The linear baseline correction treatment of data was used to reduce dispersion in thermograms. Principal component analysis of the treated and untreated data explained 96% and 89% of the data variability, respectively. Score and loading plots correlated variability between samples with change in proportion of nimodipine modifications. The R(2) for principal component regression (PCR) and partial lease square regression (PLS) were found to be 0.91 and 0.92. The root mean square of standard error of the treated samples for calibration and validation in PCR and PLS was found to be lower than the untreated sample. These models were applied to samples recrystallized from a cosolvent system, which indicated different proportion of modifications in the mixtures than those obtained by placing samples under different storage conditions. The model was able to predict the nimodipine modifications with known margin of error. Therefore, these models can be used as a quality control tool to expediently determine the nimodipine modification in an unknown mixture.

Comparison of Univariate and Multivariate Models of ¹³C SSNMR and XRPD Techniques for Quantification of Nimodipine Polymorphs.

The focus of the present investigation was to explore the use of solid-state nuclear magnetic resonance ((13)C ssNMR) and X-ray powder diffraction (XRPD) for quantification of nimodipine polymorphs (form I and form II) crystallized in a cosolvent formulation. The cosolvent formulation composed of polyethylene glycol 400, glycerin, water, and 2.5% drug, and was stored at 5°C for the drug crystallization. The (13)C ssNMR and XRPD data of the sample matrices containing varying percentages of nimodipine form I and form II were collected. Univariate and multivariate models were developed using the data. Least square method was used for the univariate model generation. Partial least square and principle component regressions were used for the multivariate models development. The univariate models of the (13)C ssNMR were better than the XRPD as indicated by statistical parameters such as correlation coefficient, R (2), root mean square error, and standard error. On the other hand, the XRPD multivariate models were better than the (13)C ssNMR as indicated by precision and accuracy parameters. Similar values were predicted by the univariate and multivariate models for independent samples. In conclusion, the univariate and multivariate models of (13)C ssNMR and XRPD can be used to quantitate nimodipine polymorphs.

The effect of emulsifying wax on the physical properties of CTAB-based solid lipid nanoparticles (SLN).

The objective of this study was to investigate the effect of cetyl alcohol (CA) and Tween® 60 (polysorbate), the primary components of emulsifying wax, on the size, zeta potential and stability of cetyltrimethyl ammonium bromide (CTAB)-based solid lipid nanoparticles (SLN) by D-optimal mixture design. A binary CTAB/polysorbate surfactant blend did not offer an advantage over a simple CTAB-stabilized SLN. This led to the conclusion that emulsifying wax could be readily substituted with CA in simple SLNs based on binary CTAB/CA blends. Polysorbate, however, may be added as a co-emulsifier to adjust the physical properties of the nanoparticles, as dictated by the formulator.

Modeling the effect of sonication parameters on size and dispersion temperature of solid lipid nanoparticles (SLNs) by response surface methodology (RSM).

The objective of this study was to evaluate the effect of sonication time and pulse frequency on average dispersion temperature (ART), particle size and zeta potential of solid lipid nanoparticles (SLNs). A two-factor, three-level response surface methodology (RSM) was used to optimize sonication time between 5 and 15 min and pulse frequency from 30 to 90%. SLNs made from stearyl alcohol (SA) and cetyl trimethylammonium bromide (CTAB) blend at 1:3 ratio were prepared by applying high-shear homogenization and sonication. Pulse frequency and time were found to have a significant effect on particle size and ART. The effect of sonication parameters on zeta potential, however, was insignificant. The optimal sonication parameters for preparing 100 nm SLNs made from a SA/CTAB blend was 60% pulse frequency at 40% power for 10 min. Optimized sonication parameters were then used to investigate the effect of lipid type on SLN size and zeta potential. The mean particle sizes of SLNs made with SA, cetyl palmitate, Precirol®, Dynasan118® and Compritol® were 98, 190, 350, 350 and 280 nm, respectively. In conclusion, pulse frequency and time were found to be critical for obtaining SLNs with desirable size, whereas the stability of the SLNs was dependent on their lipid content.

Powdered self-emulsified lipid formulations of meloxicam as solid dosage forms for oral administration.

The objectives of this study were to prepare a powdered self-emulsified (SEDDS) formulation of meloxicam and to compare its oral bioavailability against commercial Mobic tablets. The SEDDS formulation was prepared by in situ salt formation of meloxicam in a blend of lipid excipients and aqueous tris (hydroxymethyl) aminomethane solution. The liquid SEDDS was subsequently adsorbed on silica powder and was tested for size, flow, and crystal growth. The flowability index of the powdered SEDDS was borderline acceptable. Absence of crystal growth with storage was confirmed by DSC and PXRD studies. Dissolution of meloxicam from the powdered SEDDS was >90% vs. <12% for powdered meloxicam and <80% for the commercial tablets. Stability of the powdered formulations after storage in gelatin and HPMC capsules was also evaluated to study the effect of water migration from the fill into capsule shells. Capsules softened to a different extent as a function of fill material with HPMC capsules showing greater resistance to water migration. Finally, oral bioavailability of the formulations was evaluated in beagle dogs. Powdered meloxicam SEDDS formulation showed a 1.3-fold increase in AUC vs. commercial Mobic® tablets. Overall, this study described a novel SEDDS formulation of meloxicam and outlined a systematic approach to adsorbing and testing the flow and stability behavior of powdered SEDDS formulations.

Harnessing formulation and clinical pharmacology knowledge for efficient pediatric drug development: Overview and discussions from M-CERSI pediatric formulation workshop 2019.

A pediatric formulation workshop entitled "Pediatric Formulations: Challenges of Today and Strategies for Tomorrow" was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop. It provides an overview of the discussion on the interconnection of pediatric formulation design and development, clinical development strategy and pediatric clinical pharmacology. The success of pediatric drug product development requires collaboration of multi-disciplinary teams across the pharmaceutical industry, consortiums, foundations, academia and global regulatory agencies. Early strategic planning is essential to ensure alignment among major stakeholders of different functional teams. Such an alignment is particularly critical in the collaboration between formulators and clinical pharmacology teams.

Dissolution and powder flow characterization of solid self-emulsified drug delivery system (SEDDS).

In this study, the dynamics of powder flow upon griseofulvin-self-emulsified drug delivery system (SEDDS) addition to silica and silicates and the effect of these adsorbents on drug release were investigated. SEDDS was adsorbed at SEDDS/adsorbent ratios from 0.25:1 to 3:1 on magnesium aluminum silicate [5 and 80 microm], calcium silicate [25 microm], and silicon dioxide [3.6, 20, and 300 microm]. Powder flow was evaluated using the powder rheometer and compared to angle of repose. Release of drug from a 1:1 SEDDS/adsorbent powder was determined by dissolution using USP Type 2 apparatus. Powder rheometer profiles indicated that effect of SEDDS on the flow behavior of the adsorbents could be correlated to stepwise or continuous growing behavior as observed in wet granulation process. However, due to their porous nature, adsorbents exhibited an initial lag phase during which no change in flow was observed. Dissolution of drug from adsorbed-SEDDS was found to be dependent on pore length and nucleation at the lipid/adsorbent interface. Increase in dissolution rate was observed with an increase in surface area and was independent of the chemical nature of the adsorbents. Therefore, in order to manufacture free flowing powder containing liquid SEDDS, special attention should be given to particle size, specific surface area, type and amount of adsorbent.

A headspace-gas chromatography method for isopropanol determination in warfarin sodium products as a measure of drug crystallinity.

Coumadin® a nd s everal generic products of warfarin s odium (WS) contain the crystalline form (clathrate) in which WS and isopropanol (IPA) are associated in a 2:1 molar ratio. IPA is critical in maintaining the WS crystalline structure. Physicochemical properties of the drug and drug product may change when the crystalline drug transforms to amorphous form. A headspace-gas chromatography (HS-GC) method was developed and validated for IPA determination in the WS drug product. n-propanol (NPA) was used as internal standard and the method was validated for specificity, system suitability, linearity, accuracy, precision, range, limits of detection and quantification, and robustness. The method was specific, with good resolution between IPA and NPA peaks. Chromatographic parameters (retention time, IPA/NPA area ratio, tailing factor, theoretical plates, USP symmetry, capacity factor, selectivity and resolution) were consistent over three days of validation. The analytical method was linear from 2-200 µg mL-1 (0.1- 10 % IPA present in the drug product). LOD and LOQ were 0.1 and 2 µg mL-1, respectively. Accuracy at low (2 µg mL-1) and high (200 µg mL-1) IPA concentrations of the calibration curve was 103.3-113.3 and 98.9-102.2 % of the nominal value, resp. The validated method was precise, as indicated by the RSD value of less than 2 % at three concentration levels of the calibration curve. The method reported here was utilized to determine accurately and precisely the IPA content in in-house formulations and commercial products. In summary, IPA determination by HS-GC provides an indirect measure of WS crystallinity in the drug product. Nevertheless, it should be confirmed by another analytical method since IPA from the drug substance is not distinguishable from IPA that may be present outside the drug crystals in a dosage form when prepared by wet granulation with IPA.

Measurement of surface color as an expedient QC method for the detection of deviations in tablet hardness.

The objective of this study was to investigate whether a correlation exists between the surface color of tablets and their tensile strength. Theophylline powder blends with and without red dye were directly compressed into 600mg tablets. Applied compression pressure ranged from 9.3 to 271.2MPa. Colorimetric parameters: lightness (L), chromaticity (a, b), chroma (Cab), hue (hab) and color intensity (CI), were measured and recorded for both sides of each tablet using ColorQuest XE colorimeter in reflectance specular included mode. The tensile strength of the tablets was measured using a TA.XTPlus Texture Analyzer. A linear correlation was observed between the chroma (Cab) parameter and the tensile strength for each formulation of the tablets. For white tablets, the linearity was observed between Cab values ranging from 2.6 to 3.76 and tensile strength values ranging from 2.96 to 6.86MPa. For red tablets, the linearity was observed between a chroma range from 21.76 to 30.75 and tensile strength from 2.51 to 6.52MPa. A similar correlation was observed between the CI of red tablets and tensile strength. It was concluded that chroma could be used as suitable QC parameters to detect deviations in tablet hardness during bulk manufacturing.

Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets.

The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of Polyox™ based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in Polyox™ based ADF tablets increase the risk of abuse by various routes of administration.

Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations.

Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product.

Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations.

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution.

Development and validation of X-ray diffraction method for quantitative determination of crystallinity in warfarin sodium products.

The objective of this study was to develop and validate XRPD analytical method for the estimation of percent crystalline warfarin sodium present in drug products. Warfarin sodium (WS) is a clathrate containing Isopropyl alcohol entrapped in the crystalline structure. Four types of WS-excipient mixtures were prepared and used to make four formulations: M1 containing lactose monohydrate (WS: excipient 1:9), M2 containing anhydrous lactose (WS: excipient 1:9), M3 containing lactose monohydrate (WS: excipient 1:21.5), M4 containing lactose anhydrous (WS: excipient 1:21.5). Thoroughly mixed powders were packed in the XRD sample holders and diffractogram were collected. Diffractogram in the 7-9 2θ were found to be distinctive as the peak intensity grows with increasing percent crystalline WS. This peak region was, therefore, used to validate the XRPD method. Validation parameters were evaluated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantitation (LOQ). LOD and LOQ for M1, M2, M3, and M4 were 3.04, 3.17, 4.17, 4.49% and 9.21, 9.62, 12.65, 13.30%, respectively. The method was found to be linear with R(2)>0.99. With changing scan speed, X-ray power output, and type of sample holder, the method was found to be robust. Prediction of the % crystalline content of the WS sample with known crystallinity showed close agreement between actual and predicted value. In summary, XRPD method was validated, which can be used as a quantitative method for the estimation of % crystalline WS present in a drug product.

Stability characterization and appearance of particulates in a lyophilized formulation of a model peptide hormone-human secretin.

Drug shortages and recalls are often caused due to particulate growth in parenteral products and can have serious clinical implications. Root cause analysis of such recalls and shortages may arise due to insufficient understanding of process, formulations issues and environmental effects than often reported filtration and inadequate personnel training. Therefore, the goal of this study was to use a model peptide hormone, secretin that is currently under drug shortage, and investigate the effect of excipients on the lyophilized secretin formulation and evaluate the effect of storage and excursion temperatures. Lyophilized formulation was assayed for secretin by reverse phase HPLC. Solid state characteristics of lyophilized formulation were determined by X-ray powder diffraction (XRPD), thermal and spectroscopic methods. Dynamic light scattering (DLS) was used to detect particulates in the formulation after reconstitution. To assess the environmental impact, the lyophilized samples were stored at -20°C, 4°C, 25°C and 25°C/60%RH and analyzed at time 0, 1, 4, and 8 weeks. HPLC analyses exhibited a decrease in secretin concentration by 8 week (20-27% fold decrease). Visual observation and DLS showed particulates and increased reconstitution time (e.g., at 25°C/60%RH, particle size of ∼390 nm at day 0 to >2 µm as early as week 1; reconstitution time of ∼20s at day 0 to ∼67s at week 8). XRPD, thermal and spectroscopic methods demonstrated polymorphic transitions of mannitol and increased crystallinity in the lyophilized formulations with time. These studies potentially address the effect of product excursions outside the proposed label storage conditions which is -20°C for secretin formulation and this is the first time it has been investigated. These observations indicate that both environmental factor and excipient may have an impact on the stability of secretin formulation and appearance of particles in the product.

Comparison of X-ray powder diffraction and solid-state nuclear magnetic resonance in estimating crystalline fraction of tacrolimus in sustained-release amorphous solid dispersion and development of discriminating dissolution method.

The focus of present investigation was to explore X-ray powder diffraction (XRPD) and solid-state nuclear magnetic resonance (ssNMR) techniques for amorphous and crystalline tacrolimus quantification in the sustained-release amorphous solid dispersion (ASD), and to propose discriminating dissolution method that can detect crystalline drug. The ASD and crystalline physical mixture was mixed in various proportions to make sample matrices containing 0%-100% crystalline-amorphous tacrolimus. Partial-least-square regression and principle component regression were applied to the spectral data. Dissolution of the ASD in the US FDA recommended dissolution medium with and without surfactant was performed. R(2) > 0.99 and slope was close to one for all the models. Root-mean-square of prediction, standard error of prediction, and bias were higher in ssNMR-based models when compared with XRPD data models. Dissolution of the ASD decreased with an increase in the crystalline tacrolimus in the formulations. Furthermore, detection of crystalline tacrolimus in the ASD was progressively masked with an increase in the surfactant level in the dissolution medium. XRPD and ssNMR can be used equally to quantitate the crystalline and amorphous fraction of tacrolimus in the ASD with good accuracy; however, ssNMR data collection time is excessively long, and minimum surfactant level in the dissolution medium maximizes detection of crystalline reversion in the formulation.