An advanced automation platform coupled with mass spectrometry for investigating in vitro human skin permeation of UV filters and excipients in sunscreen products.

RATIONALE: Systemic absorption of UV-filtering chemicals following topical application of sunscreens may present a safety concern. The Food and Drug Administration (FDA) had recommended an in vitro skin permeation test (IVPT) to evaluate the potential of this safety risk for the evaluation of sunscreens prior to clinical studies. Therefore, a sensitive and robust bioanalytical method(s) were required for IVPT studies of different topical sunscreen products. METHODS: An analytical procedure to quantitate sunscreen UV-filtering components and excipients in IVPT samples including avobenzone, octocrylene, oxybenzone, ecamsule, methylparaben and propylparaben was developed employing a RapidFire 360 robotic sample delivery system coupled with a triple quadrupole mass spectrometer. The analytical procedure was developed and validated according to the requirements of the FDA Bioanalytical Method Validation Guidance for Industry (2018). RESULTS: The analytical method provided a turnaround time of 12 seconds per sample and was determined to be accurate, precise, specific, and linear over the corresponding analytical ranges. The validated method was successfully applied for two IVPT studies for evaluating the skin permeation potential of UV-filtering chemicals and assisting with the selection of the sunscreen products for the clinical study conducted by the FDA. CONCLUSIONS: This work highlights the first analytical procedure that has applied a non-chromatographic-MS/MS automation platform to an in vitro biopharmaceutics study. The analytical platform simultaneously quantitated four UV filters and two excipients in complex media to evaluate their permeation in IVPT studies. The sample throughput and analytical performance of advanced automation platforms indicate their analytical procedure has the potential to significantly advance the efficiency of IVPT studies to evaluate permeation of a wide variety of UV chemical filters and excipients for topical OTC sunscreen products.

Identification of critical formulation parameters affecting the in vitro release, permeation, and rheological properties of the acyclovir topical cream.

To understand effects of formulation variables on the critical quality attributes (CQA) of acyclovir topical cream, this study investigated effects of propylene glycol (PG), poloxamer, and sodium lauryl sulfate (SLS) concentrations, acyclovir particle size, and formulation pH of the acyclovir cream. Fifteen formulations were prepared and characterized for rheological properties, particle size distribution, drug release and in vitro skin permeation. Drug distribution between various phases of the cream was determined. The concentration of soluble acyclovir in the aqueous phase was determined as a surrogate of the equilibrium with other acyclovir species in the cream. The interaction among effects of the formulation variables on the amount of acyclovir retained by skin was also evaluated. The results showed that PG significantly (p < 0.05) increased the yield stress, viscosity, drug concentration in the aqueous phase, and drug release. The PG and SLS significantly (p < 0.05) increased acyclovir retention by skin samples. Particle size of acyclovir inversely affected the drug release. This study revealed that the employed concentrations of PG and SLS and particle size of the dispersed acyclovir are critical formulation variables that should be carefully controlled when developing acyclovir topical creams with desired performance characteristics.

In Vitro Testing of Sunscreens for Dermal Absorption: A Platform for Product Selection for Maximal Usage Clinical Trials.

Sunscreen products contain UV filters as active ingredients for the protection of the skin against UVR. The US Food and Drug Administration (FDA) issued a new proposed rule in 2019 (84.FR.6204) for sunscreens and identified the need for additional safety data for certain UV filters including their dermal absorption data. Dermal absorption data reveal systemic exposure of UV filters in humans, which can be obtained from clinical maximal usage trials. FDA guidance recommends conducting in vitro skin permeation tests (IVPTs) to help select formulations for maximal usage clinical trials as IVPT results may be indicative of in vivo absorption. This case study reports in vitro methodologies used for the selection of sunscreen products for an FDA-sponsored proof-of-concept maximal usage clinical trial. An IVPT method was developed using human cadaver skin. Commercially available sunscreen products were tested to determine the skin absorption potential of common UV filters using the IVPT. All the studied sunscreen products demonstrated a certain degree of skin absorption of UV filters using IVPT, and a formulation rank order was obtained. These sunscreen products were also characterized for several formulation properties including the globule size in emulsions, which was found to be an indicator for the rank order.

Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing.

A continuous processing platform was developed to produce polymeric micelles. A block copolymer of mPEG (5kD)-PCL (2kD) was used as the model drug carrier. The polymeric micelles were produced using an innovative co-axial turbulent jet with co-flow continuous technology to precisely control the physicochemical properties of the micelles. A 3 × 3 × 4 full factorial design of experiment (DoE) study was conducted to optimize the polymeric micelle processing to achieve the desired critical quality attributes such as particle size and polydispersity index (PDI). Curcumin was used as a hydrophobic model drug as polymeric micelles are traditionally used to improve solubility and chemical stability of hydrophobic drug molecules. A second DoE study was conducted to achieve maximal drug loading. The average size of the optimized curcumin-loaded polymeric micelles was 29.1 ± 0.51 d.nm with a PDI value in the range of 0.05 ± 0.02 and a maximum drug loading of 11.1 ± 0.81% (w/w). When compared to polymeric micelles prepared using a manual ethanol injection method the particle size, PDI and drug loading for curcumin-loaded polymeric micelles was 74.8 ± 8.68 d.nm, and 0.46 ± 0.12 and 8.12 ± 1.23%, respectively. These data show that the continuous processing method provided significant improvement in controlling the key quality attributes. The curcumin-loaded polymeric micelles exhibited a sustained release profile during dissolution of about 50% drug released in 12 h compared to the free drug, which was completely released within 10 h. The curcumin-loaded polymeric micelles were characterized for other key quality attributes such as critical micelle concentration (CMC), and morphology by transmission electron microscopy, X-ray powder crystallography, polarized light microscopy, and differential scanning calorimetry. A novel method for determining the CMC of the polymer was developed using dynamic light scattering (DLS). Curcumin-loaded polymeric micelles were further processed by lyophilization to prevent hydrolytic cleavage of the polymers and maintain long term stability. The current study highlighted the potential advantages of transitioning from manual batch processing to continuous processing and serves as an example of improving processing efficiency as well as product quality through utilization of advanced processing technologies.

Drug recrystallization in drug-in-adhesive transdermal delivery system: A case study of deteriorating the mechanical and rheological characteristics of testosterone TDS.

This study investigated the effects of drug recrystallization on the in vitro performance of testosterone drug-in-adhesive transdermal delivery system (TDS). Six formulations were prepared with a range of dry drug loading in the adhesive matrix from 1% to 10% w/w with the aim of generating TDS with various levels of drug crystals. We visually quantified the amount of crystals in TDS by polarized light microscopy. The effect of drug recrystallization on adhesion, tackiness, cohesive strength, viscoelasticity, drug release, and drug permeation through human cadaver skin were evaluated for these TDS samples. The Optical images showed no crystals in 1% and 2% testosterone TDSs; however, the amount of crystals increased by increasing testosterone loading from 4 to 10%. A proportional and significant decrease (p < 0.05) in tack, peel, and shear strength of the adhesive matrix with increasing amount of crystals in TDS was observed. The drug crystals resulted in a proportional deterioration of the viscoelastic properties of the adhesive matrix. The 2% testosterone TDS showed faster drug release rate when compared to 1% testosterone TDS. The increase in drug loading from 2% to 4% w/w slightly increased the cumulative amount of testosterone released. Further increase in drug loading in TDS to 6, 8, and 10% was nonsignificant (p > 0.05) to affect the drug release and permeation. In conclusion, this study demonstrated that the extent of drug recrystallization can be quantitatively correlated with the deterioration of performance characteristics of TDS products.

Assessing Drug Release from Manipulated Abuse Deterrent Formulations.

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106-500 µm) and coarse (500-1000 µm) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3-5 kDa to 12-14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.

Zinc supplementation improves the harvest purity of ß-glucuronidase from CHO cell culture by suppressing apoptosis.

The variability of trace metals in cell culture media is a potential manufacturing concern because it may significantly affect the production and quality of therapeutic proteins. Variability in trace metals in CHO cell culture has been shown to impact critical production metrics such as cell growth, viability, nutrient consumption, and production of recombinant proteins. To better understand the influence of excess supplementation, zinc and copper were initially supplemented with 50-µM concentrations to determine the impact on the production and quality of ß-glucuronidase, a lysosomal enzyme, in a parallel bioreactor system. Ethylenediaminetetraacetic acid (EDTA), a metal chelator, was included as another treatment to induce a depletion of trace metal bioavailability to examine deficiency. Samples were drawn daily to monitor cell growth and viability, nutrient levels, ß-glucuronidase activity, and trace zinc flux. Cell cycle analysis revealed the inhibition of sub-G0/G1 species in zinc supplemented cultures, maintaining higher viability compared to the control, EDTA-, and copper-supplemented cultures. Enzyme activity analysis in the harvests revealed higher specific activity of ß-glucuronidase in reactors supplemented with zinc. A confirmation run was conducted with supplementations of zinc at concentrations of 50, 100, and 150 µM. Further cell cycle analysis and caspase-3 analysis demonstrated the role of zinc as an apoptosis suppressor responsible for the enhanced harvest purity of ß-glucuronidase from zinc-supplemented bioreactors.

Evaluation of commercially available meth-deterrent pseudoephedrine hydrochloride products.

Pseudoephedrine (PSE) extracted from its dosage forms can be used as the starting material to prepare methamphetamine by drug abusers. Recently, some pseudoephedrine drug products marketed under the over the counter (OTC) monograph have been promoted as 'meth-deterrent'. The goal of this investigation was to evaluate the extraction and dissolution of these product against controls of non-meth-deterrent products of pseudoephedrine. Immediate release (IR) PSE OTC Product-C, Product-D and Product-E with meth-deterrent claim on their packaging were selected for this study. Accordingly, OTC IR PSE tablet Product-A and OTC extended release (ER) PSE tablet Product-B, with no meth-deterrent claims, were used as controls. The extraction studies were performed on intact tablets or capsules and on manipulated products employing water, ethanol and 0.l N HCl as solvents. The extraction studies were also performed in water at elevated temperatures by heating the water in an oven and in a microwave. The dissolution studies were performed in water and 0.1 N HCl. The amount of PSE extracted from Product-C was found similar to the amount extracted from the non-meth-deterrent control Product-A. The amount of PSE extracted from Product-D and Product-E was found lower than the amount extracted from control Product-A under the conditions studied. Product-A, Product-B, and Product-C met their respective dissolution acceptance criteria. The IR Products D and E released less than 50% drug in 12 h and did not meet either IR or ER PSE tablet USP dissolution acceptance criteria. In summary, the extraction of Product-C was found to be high (approximately 85% in 30 min) and was similar in extraction to the control Product-A. The extraction of Product-D and Product-E was found less than the extraction of control Product-A. Also, Product-D and Product-E did not exhibit complete drug release. This study showed that PSE can be extracted from Product D and Product E.

Understanding drug distribution and release in ophthalmic emulsions through quantitative evaluation of formulation-associated variables.

Establishing bioequivalence (BE) of ophthalmic emulsions in the absence of in vivo data is challenging. In these emulsions, drug release is a complex process due to drug distribution among various phases which are difficult to characterize. The objective of this study is to investigate the process of drug distribution and mechanism of drug release in the context of formulation-associated variables. A previously reported kinetic method for determining drug partitioning was used to quantitatively evaluate the drug distribution within a simplified biphasic (emulsion) system employing cyclosporine and difluprednate as model drugs. The impacts of formulation variables, such as the amount of polysorbate 80, glycerin, and carbomer copolymer as well as the area of oil-water interface were investigated. Polysorbate 80 was found to have the greatest influence on the drug distribution. It enhanced both the rate and extent of the drug distribution from oil to aqueous phase. Glycerin was found to slightly reduce the rate and extent of drug distribution of cyclosporine into the aqueous phase, probably by suppressing the solubilization capability of the micelles. Carbomer slowed down the diffusion of drug into the oil phase and shifted the equilibrium drug distribution towards the aqueous phase. Furthermore, increase in the interfacial area significantly increased the rate of drug diffusion across the oil-aqueous interface but had negligible effect on the extent of drug distribution. It is noteworthy that the experimental setup utilized a planar interface rather than an interface with curvature, which may have slightly underestimated the influence of globule size on equilibrium drug distribution. The findings of this study give insight into the drug distribution and diffusion in complex ophthalmic emulsions and assist with formulation design as well as development of in vitro methods to support BE assessment of ophthalmic emulsions.

Quality attributes and evaluation of pharmaceutical glass containers for parenterals.

Pharmaceutical containers for parenterals have been predominantly manufactured using glass as a packaging material of choice, especially Type-I glass, since it has been regarded as a chemically inert and an effective container closure system (CCS). Nevertheless, there have been reports and recalls related to glass quality issues, such as breakage, flakes, and particles observed in marketed products. The novelty of this research is based on the knowledge gathered from our previously conducted risk assessments and establishing a comprehensive testing platform focused on risk factors for glass container failure modes and applicability to other types of pharmaceutical containers. The evaluation of container quality attributes was performed for three model glass vials using a mechanical and chemical durability testing platform: freeze-thaw, lyophilization, compression, scratch tests; visual inspection, pH, particle size analyses, extractable, leachable and imaging studies that were conducted under normal (4 and 25 °C), and stress condition (60 °C), respectively. The performance between the glass containers tested under certain stress conditions (failure modes) were variable and differentiated. The systematic platform testing approach shows the importance of lab-based risk evaluation in assessing common failure modes of pharmaceutical containers, since the quality attributes for injectable products are complex and can impact final product quality.

Development and applications of a material library for pharmaceutical continuous manufacturing of solid dosage forms.

The purpose of this study is to establish a material library and discuss its potential application to the development and lifecycle management of a continuous manufacturing process for solid dosage forms. Particularly, this study addresses the importance of selecting process-relevant testing conditions for material characterization, proposes a methodology to capture relevant information with a reduced set of measurements, and correlates material properties with process performance. This study included 20 pharmaceutical materials, and each material was characterized by 44 properties, capturing 880 data points. The stress conditions of a commonly used feeder hopper were calculated using the Janssen model for six selected materials. Multivariate analysis, such as principal component analysis and clustering analysis, was used to explore the knowledge space of the material library. Statistically similar and dissimilar material properties were evaluated for material feeding performance from a loss-in-weight feeder to test utility of the material library. 20 materials included in this study show a wide range of material properties. Consolidation stress during testing significantly impacts obtained material properties. Based on a material similarity metric, a reduced set of characterization tests that captures >95% of the relevant information was identified. Materials were then grouped into six clusters. The material loss-in-weight feeding results show that the materials within the same cluster show similar feeding performance, while selected materials from different cluster have different feeding performance. Additional material understanding regarding flow properties may be needed to implement a continuous manufacturing process. Characterization using multiple tests under process-relevant conditions can be helpful to establish the correlation between material properties and process and product performance using multivariate analysis tools.

A Kinetic Approach to Determining Drug Distribution in Complex Biphasic Systems.

Pharmaceutical emulsions contain multiple components, such as micellar, aqueous, and oil phases, leading to complex drug transfer and equilibrium phenomena. These complex components present challenges for the bioequivalence assessment of the drug products. The objective of the study was to develop a method that can probe the underlying mechanism and process of drug distribution. The concept of drug partitioning into biphasic systems was used to simplify the complex transfer phenomenon. A kinetic method was developed taking into account the biphasic diffusion. Using this approach, both the rate (kinetics) and the extent (equilibrium) of distribution can be determined. For method development purpose, 3 model compounds (triamcinolone acetonide, difluprednate, and cyclosporine), with expected partition coefficient values ranging from 2 to 6, were tested using the kinetic method and the traditional shake-flask method. The values obtained by the 2 methods for all compounds correlated well (r2 = 0.825). Various organic and aqueous solvents which are commonly encountered in formulations were also tested to determine the impact of phase composition on drug distribution. The kinetic method was found to offer more flexibility in terms of solvent composition and can lead to better understanding for drug distribution and potential drug release in complex biphasic systems.

Extrudability analysis of drug loaded pastes for 3D printing of modified release tablets.

The rheological characteristics of pastes for 3D printing of tablets may not be described fully by the traditional rheological tests generally used for other pastes. In the present study, extrudability testing of carbopol based 3D printing pastes was performed to establish a constitutive rheological model for micro-extrusion. This model was developed for pastes that exhibit a non-linear plasto-viscoelastic behavior and follow the generalized Herschel-Bulkley flow rule. An analytical model was applied to extrudability data obtained by micro-extrusion through nozzles of 0.4 and 0.6 mm diameters. For this purpose, nineteen pastes were prepared per a fractional factorial design using various concentrations of the active ingredient and soluble and insoluble excipients. Critical material parameters (σ0, k and n) of the pastes were then calculated by analyzing extrudability data using a constitutive equation relating flow rate, nozzle and cartridge diameters, printing pressure and slip-flow angle. The accuracy of the constitutive model to predict paste yield stress, consistency and flow indices was evident by low RMSE values of 0.0691 bar, 0.034 and 6.3 bar/sn, respectively. Yield stress, flow and consistency parameters of the pastes were significantly affected by percentages of soluble and swellable excipients. The nozzle diameter had significant effect on flow index (n) but not on the consistency index (k). Hence, this study provides a mechanistic model to characterize the complex rheological behavior of pastes for 3D printing of tablets by a micro-extrusion process.

Development of mechanistic models to identify critical formulation and process variables of pastes for 3D printing of modified release tablets.

The future of pharmaceutical manufacturing may be significantly transformed by 3-dimensional (3D) printing. As an emerging technology, the indicators of quality for materials and processes used in 3D printing have not been fully established. The objective of this study was to identify the critical material attributes of semisolid paste formulations filled into cartridges for 3D printing of personalized medicine. Nineteen semisolid formulations were prepared per a fractional factorial design with three replicates of the center point. The variables investigated included percent loading of API and various soluble and insoluble excipients. Pastes were characterized for viscoelastic characteristics during the 3D printing process including creep recovery, cross-modulus and extrudability models. Packing efficiency of pastes into 3D printing cartridges was also evaluated by X-ray tomography. Changes in composition of 3D printing pastes resulted in significant variations in their viscoelastic parameters, namely their elastic deformation, flow and relaxation behaviors. The percent of soluble excipients incorporated was the most significant factor affecting the creep behavior of pastes. Cross-over stresses were assessed to indicate the minimum pressure needed for the pastes to initiate flow. Increasing solid and swellable contents of the pastes from 7% to 63% w/w increased significantly (p < 0.05) the cross-over stress from 0.93 × 10-3 Pa to 9.47 × 10-3 Pa. Increasing soluble ingredients of paste from 30% to 80% w/w was found to increase flow of the paste from 0.41 × 10-3 to 3.85 × 10-3 %/s. X-ray tomography images revealed inclusion of air bubbles during packing of pastes into cartridges. These bubbles may affect the relaxation behavior of the pastes; hence bubbles should be eliminated. This study unveiled the critical material attributes that could be controlled for consistent 3D printing by microextrusion.

Application of in vitro lipolysis for the development of oral self-emulsified delivery system of nimodipine.

The objective of the current study was to optimize for the first time the formulation variables of self-emulsified drug delivery system (SEDDS) based on drug solubilization during lipolysis under a biorelevant condition of digestion such as lipase activity, temperature, pH, fed-fasting state, etc. Nimodipine (ND), a BCS class II, was used as a model drug to prepare the SEDDS. Various oils, surfactants, and cosurfactants were screened for their solubilization potential of ND. Area of self-emulsification was identified using various ternary phase diagrams. Box-Behnken design was employed to investigate effects of formulation variables on various dispersion, emulsification, and lipolysis characteristics of SEDDS. Among 26 candidate formulations, highest ND solubility of 12.72%, 11.09% and 11.2% w/w were obtained in peppermint oil as the oily phase, Cremphor EL as the surfactant and PEG400 as the cosurfactant, respectively. Cremphor EL was the most significant factor to decrease SEDDS droplet size to 30.16 nm. On the other hand, increasing the oil concentration was found to significantly increase the polydispersity index up to 0.31. A faster emulsification rate of 3.37%/min was obtained at higher Cremphor El/PEG 400 ratio. Increasing the percentage of lipid components of SEDDS resulted in lower rate of lipolysis with less recovery of ND in aqueous phase. Under fed state, percentage of lipolysis of optimized formulation was less than that observed under fasted state. However, lowest rate and percentage of lipolysis were observed in lipolysis media without phospholipids and bile salts. Hence, this study demonstrated that in vitro lipolysis could be used as a surrogate approach to distinguish effects of formulation variables on fate of SEDDS upon digestion. Further studies are in progress to identify the lipolytic products of the employed excipients by LC-MS/MS.

Analytical considerations for measuring the globule size distribution of cyclosporine ophthalmic emulsions.

Measurement of particle size and size distribution of complex drug products exhibiting complex rheological behaviors can be challenging as these properties may be beyond the theoretical assumptions of the measurement technique. Herein cyclosporine (CsA) ophthalmic emulsion was selected as a model complex system, and an in-depth assessment of particle size was performed using five fundamentally different particle sizing techniques, including dynamic light scattering (DLS), laser diffraction (LD), nanoparticle tracking analysis (NTA), cryogenic transmission electron microscopy (Cryo-TEM) and 2-dimensional diffusion ordered spectroscopy nuclear magnetic resonance (2D DOSY-NMR). The effect of various viscosity modifying and stabilizing excipients in the emulsions was assessed using four types of CsA formulations, i.e., 1) no viscosity modifying excipients, 2) carbomer copolymer type A (CCA), 3) Carbopol 1342, or 4) hydroxypropyl methyl cellulose (HMPC). In general, the variability of reported particle size increased, and is not as accurate, for emulsions dispersed in a non-Newtonian fluid and at higher emulsion concentrations. This effect was reduced in part by diluting the samples to lower volume fraction and a more Newtonian regime. To address the concern that sample dilution prior to measurement may induce physical instability in the emulsions, NTA was used to monitor average size at dilutions of up to 1:50,000. The size was found to remain constant and independent of the presence or type of stabilizer used. Cryo-TEM further confirmed that dilution did not alter particle size or morphology. Of the five evaluated techniques, Cryo-TEM and 2D DOSY NMR did not require dilution for measurement. The overestimate in DLS size measurements for certain CsA formulations was attributed to complex dispersant rheological behavior, particle-particle interactions, multiple light scattering events, and/or scattering interference from the polymers, which can be overcome by either testing under dilutions or by selecting one of the techniques less impacted by the interference of polymer.

Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments.

The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed to have minimal impact. An evaluation of the release mechanism of cyclosporine from the ointment revealed an interplay between formulation (e.g. physicochemical properties of the drug and ointment matrix type) and the release medium. These data provide a scientific basis to guide method development for in vitro drug release testing of ointment dosage forms. These results demonstrate that the in vitro methods used in this investigation were fit-for-purpose for detecting formulation and process changes and therefore amenable to assessment of product sameness.

Asymmetric flow field flow fractionation for the characterization of globule size distribution in complex formulations: A cyclosporine ophthalmic emulsion case.

Commonly used characterization techniques such as cryogenic-transmission electron microscopy (cryo-TEM) and batch-mode dynamic light scattering (DLS) are either time consuming or unable to offer high resolution to discern the poly-dispersity of complex drug products like cyclosporine ophthalmic emulsions. Here, a size-based separation and characterization method for globule size distribution using an asymmetric flow field flow fractionation (AF4) is reported for comparative assessment of cyclosporine ophthalmic emulsion drug products (model formulation) with a wide size span and poly-dispersity. Cyclosporine emulsion formulations that are qualitatively (Q1) and quantitatively (Q2) the same as Restasis® were prepared in house with varying manufacturing processes and analyzed using the optimized AF4 method. Based on our results, the commercially available cyclosporine ophthalmic emulsion has a globule size span from 30 nm to a few hundred nanometers with majority smaller than 100 nm. The results with in-house formulations demonstrated the sensitivity of AF4 in determining the differences in the globule size distribution caused by the changes to the manufacturing process. It is concluded that the optimized AF4 is a potential analytical technique for comprehensive understanding of the microstructure and assessment of complex emulsion drug products with high poly-dispersity.

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.