Abstracts for Posters 9-17
Poster 9
Accelerated Stability Assessment Program (ASAP) Study of Peroxides in Excipients
Ridhima Shrestha, Jesse D. Scalesi, Louis Somma, Maria J. Krisch, and Kenneth C. Waterman
FreeThink Technologies, Inc.
Presenting Authors: Jesse D. Scalesi and Louis Somma, [email protected] and [email protected]
Corresponding Author: Maria J. Krisch, [email protected]
Purpose
Peroxides contribute to oxidative degradant formation in many pharmaceutical products. Peroxides can be introduced into pharmaceutical formulations as excipient process impurities, by peroxides that grow during excipient storage, and in the drug products themselves during shelf life. This study generates a predictive model for peroxides in several common excipients through a systematic understanding of the temperature and humidity dependence of this behavior.
Methods
Four different excipients—HPMCAS, HPC, and two types of povidones (Kollidon® 30, and Plasdone™ K-29/32)—were placed into canning jars and exposed to constant temperature and relative humidity stress conditions for up to 21 days. Stress conditions ranged from 60–90°C and 3–28% relative humidity, controlled by saturated salt solutions. Selected samples were stressed in parallel at low oxygen conditions. Peroxide growth was measured through the FOX2 peroxide assay using calibrated visible absorbance at 560 nm. The data are expressed in ppm, assuming that all peroxides measured are hydrogen peroxide.
Results
Peroxide growth in HPMCAS, Kollidon® 30, and Plasdone™ K-29/32 is well fit by a moisture-modified Arrhenius equation with average temperature dependences (Ea of 23–25 kcal/mol). All peroxides tested show a negative dependence on relative humidity, likely due to secondary degradation. Kollidon® 30 and Plasdone™ K-29/32 show the fastest peroxide growth as compared to HPC and HPMCAS. As expected, in the absence of oxygen, growth of peroxides with all excipients is repressed.
Conclusion
A model is demonstrated to quantify the temperature and relative humidity dependence of peroxide growth for four excipients. In contrast to the stability behavior of most materials, peroxide accumulation will be more significant under drier conditions.
Poster 10
Innovative Thermosensitive Hydrogel for Probiotic Delivery in Reproductive Tract Diseases: Enhancing Stability and Antibacterial Efficacy
Feng Zhou and Jiantao Zhang
Chinese Academy of Sciences
Presenting and Corresponding Author: Jiantao Zhang, [email protected]
Purpose
Bacterial reproductive tract diseases, caused by microbiota imbalances, lead to inflammation and complications such as preterm birth. Traditional probiotic delivery methods face challenges with adhesion, stability, and patient comfort. We developed a novel dual-chamber syringe system that separately stores liquid and solid probiotic formulations, mixing them just before use to form a water-based hydrogel. This in situ formation preserves probiotic viability, extends shelf life, and enhances therapeutic efficacy, offering a promising solution for restoring microbial balance and treating reproductive tract infections.
Methods
The liquid formulation was prepared by dissolving Poloxamer 407 in deionized water at various concentrations (15–24 wt%) and refrigerating overnight. Probiotic strains (Lactobacillus paracasei, Lactobacillus rhamnosus, and Bifidobacterium infantis) were cultured in MRS broth, incubated, and centrifuged to obtain bacterial pellets.
For solid formulations, probiotic pellets were mixed with excipients (maltodextrin, trehalose, sodium alginate, fumed silica, and inulin) under nitrogen. Alternative formulations involved mixing probiotics with inulin, maltodextrin, trehalose, and skim milk powder, followed by freeze-drying and milling. A dual-chamber syringe was used to combine the liquid and solid formulations, forming a probiotic-loaded hydrogel upon compression.
Results
The probiotic gel exhibited excellent batch-to-batch uniformity, maintaining activity for at least six months, whereas pure probiotic powder lost over 90% viability in two weeks. Antibacterial assays showed over 95% inhibition against four pathogens after six months of storage. Inhibition zone assays confirmed strong antibacterial efficacy, with active probiotic gels forming larger, clearer inhibition zones than inactivated gels. The gel technology was successfully applied to Lactobacillus rhamnosus and Bifidobacterium infantis, which maintained high viability for two months at 4°C and nearly 100% inhibition against Escherichia coli, Staphylococcus aureus, Candida albicans, and Gardnerella. Switching from a V-type mixer to an encapsulation mixing method improved uniformity.
Conclusion
Our dual-chamber syringe system enables in situ probiotic gel formation, ensuring long-term stability and high antibacterial efficacy, making it a promising platform for treating bacterial reproductive tract diseases.
Poster 11
Influence of Terminal Groups on PLGA Degradation and Their Role in the Sustained Release of Cyproterone Acetate
Qien Zhao, Junhui Yang, Jialin Liu, Shengyu Zhang, Wei Zhaob, Wenting Jiang, Hongxuan Yang, Yang Zhou, Lei Jiang, Jiantao Zhang
Chinese Academy of Sciences
Presenting and Corresponding Author: Jiantao Zhang, [email protected]
Purpose
This study aims to synthesize poly(lactic-co-glycolic acid) (PLGA) with varying terminal groups and bridge the knowledge gap on how the carbon chain length of these groups influences the degradation rates and drug release profiles of PLGA microspheres
Methods
In this study, four distinct PLGA polymers with different terminal groups (acid, n-hexanol, dodecanol, and hexadecanol) were synthesized, each with a molecular weight (Mw) of approximately 15,000, a lactic acid/glycolic acid (L/G) ratio of 74/26, and an inherent viscosity of 0.19 dL/g. A novel terminal group analysis method was developed to precisely characterize terminal group properties in PLGA, representing a significant advancement over traditional methods. Microspheres were prepared using the conventional oil-in-water (O/W) emulsion solvent evaporation method, in which a dichloromethane solution containing PLGA and cyproterone acetate (CYA) was injected into an aqueous polyvinyl alcohol solution to form an O/W emulsion. The study examined the impact of terminal group modifications on the degradation kinetics and drug release behavior of CYA-loaded microspheres, which were further characterized for volume mean diameter, drug loading rate, and encapsulation efficiency.
Results
The values for Mw, PDI, and inherent viscosity were found to be similar across all four PLGAs. The microspheres exhibited a volume mean diameter of 9 to 11 µm, a drug loading rate of approximately 10%, and an encapsulation efficiency of about 97%. The study demonstrated that terminal group length plays a crucial role in modulating the drug release profile, with the time to 50% release following this order: acid (~8 days) < n-hexanol (~9 days) < dodecanol (~14 days) < hexadecanol (~29 days). These findings underscore the significant impact of terminal group modifications on the degradation and drug release behavior of PLGA microspheres.
Conclusion
This study provides valuable insights into how variations in PLGA terminal groups can be leveraged to optimize drug release mechanisms, contributing to the development of advanced pharmaceutical excipients. The novel terminal group analysis method introduced here serves as a crucial tool for future research on PLGA modifications, enhancing the predictability and control of drug release in PLGA-based systems. These findings are expected to have a significant impact on the design of long-acting injectable formulations and other controlled-release applications.
Poster 12
Non-gelatin Film Coatings for Formulating Easy-to-Swallow Tablets
Kun Chen, Ming Ji, Nitin Kumar Swarnakar, Ashish Ashok Joshi, and Sandip Tiwari
BASF Corporation
Presenting Author: Kun Chen, [email protected]
Corresponding Author: Nitin Kumar Swarnakar, [email protected]
Purpose
A survey of literature shows that up to 40% of the general population has trouble swallowing medicines [1]. Gelatin-based tablet coatings facilitate ease of swallowing; however, they could cause stomach upset, heartburn, allergies, and possibly interaction with the active pharmaceutical ingredient (API) [2]. The animal origin of gelatin results in variability in molecular weight, bloom strength, and functional properties as well as raising BSE/TSE concerns[3]. Aqueous solutions of gelatin are not easy to handle due to the foaming and may result in stability issues for water- or oxygen-sensitive APIs. This study focuses on the use of compendial Kollicoat® IR (PEG-PVA graft copolymer - USP, EP) and Kollicoat® Protect (Kollicoat® IR + PVA), polymeric coating as effective alternatives to gelatin-based coating in formulating “easy-to-swallow” tablets. Additionally, such non-gelatin coatings offer good oxygen and moisture barrier properties without the risk of development of peroxides during storage.
Methods
Core tablet(s) (680 mg) consisting of 250 mg acetaminophen, 250 mg aspirin, 65 mg caffeine, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate, were manufactured by granulation followed by lubrication and compression. They were seal coated using PEG-PVA graft copolymer and PVA (6:4) (3% weight gain) followed by second layer of PEG-PVA graft copolymer (5% weight gain), both at 60 °C inlet temperature. Tablet slip performance, which evaluates ease of swallowing, was characterized using the method derived from static and dynamic friction test [4]. Each tablet was dipped into water for 1sec and placed on a Formica® laminated flat surface at different slope angles to evaluate the distance that each tablet slides down on the surface (Figure 3). Water vapor transmission rate (WVTR) and oxygen gas transmission rate (OGTR) were determined using isolated films of comparable thicknesses (70–75 μm), prepared using a Coatmaster™. To prevent sedimentation during the drying phase, the dispersions were cast in 3-4 thin layers (one on top of the other) depending on the pigment content and the film density.
The WVTR of PEG-PVA graft copolymer and PVA (6:4) was evaluated previously vs. PVA and HPMC using ASTM F 1249-20 [5] wherein a dry and wet chamber of known temperature and humidity are separated by the barrier film to be tested. Water vapor passing through the film mixes with gas in the dry chamber and is carried to a pressure modulated IR sensor, which generates an electrical signal proportional to the moisture content. The OGTR of PEG-PVA graft copolymer and PVA (6:4) and PEG-PVA graft copolymer were evaluated vs. PVA, HPC EF, and HPMC, using ASTM D 3985-17, in which the test sample is equilibrated in an environment with <1% relative humidity. The specimen is then mounted as a sealed semi-barrier between two chambers at ambient atmospheric pressure. One chamber is purged by a stream of nitrogen and the other chamber contains oxygen. As oxygen permeates through the film into the nitrogen carrier gas, it is transported to the coulometric detector where it produces an electrical current, the magnitude of which is proportional to the amount of oxygen flowing into the detector per unit time.
Results
PEG-PVA graft copolymer and PVA (6:4) seal-coating with high pigment concentration provides good moisture barrier properties, ideal for improving stability of moisture-sensitive APIs [6]. It can hold up to 75% pigment relative to the polymer, which is significantly higher than HPMC based coatings and easier to formulate than PVA based coatings. In addition, this coating exhibits excellent oxygen barrier properties. Tablets coated with PEG-PVA graft copolymer and PVA (6:4) alone showed improved slip performance vs. uncoated tablets which didn’t slide at a slope of 45o or lower. However, it was not equivalent to the marketed gelatin-coated tablet, possibly due to friction generated by talc present in the PEG-PVA graft copolymer and PVA (6:4) coating. To further improve the slip performance, a second coating layer of PEG-PVA graft copolymer was applied over the PEG-PVA graft copolymer and PVA (6:4) coated tablets. PEG-PVA graft copolymer is a water-soluble film former for instant release coatings. It is an excellent wet binder, and easily processed due to low solution viscosity (260 mPas of 25% solution), and very fast dissolution. When stored over 18 months under accelerated stability storage conditions, this polymer did not generate any peroxides (Data not shown). The two-layer coated tablets showed improved slip performance (slope as low as 15o) compared to gelatin coated marketed tablets. The minimum sliding force for the two-layer coated tablet is also lower than that of gelatin-coated market standard.
Conclusion
Gelatin-based tablet coatings use complicated manufacturing process and present issues with handling, stability, and consumer acceptance. The proposed dual-layer coated tablets (copolymer of PEG-PVA graft copolymer and PVA (6:4) followed by PEG-PVA graft copolymer) may serves as an improved non-gelatin alternative for greater ease of swallowing. Additionally, it offers better moisture protection in contrast to a standard film-coating. Further studies in clinical set up will help confirm the ease of swallowing and patient compliance.
Poster 13
Validating metabolic relevance of Nw-hydroxy L-Arginine to inflammatory and immune-checkpoint molecules based on breast cancer estrogen-receptor status
William Speltz, Megan Steele, Connor LaBonte, and Srinidi Mohan
University of New England
Presenting and Corresponding Author: Srinidi Mohan, [email protected]
Purpose
We have previously delineated Nw-hydroxy L-Arginine, (NOHA) as a predictive biomarker in distinguishing breast cancer based on estrogen-hormone-receptor status (USPTO 10,073,099), and on its utility with disease screening, as well as with high-risk breast cancer treatment response and therapy monitoring. In this study, we compare NOHA response with estrogen-receptor status selective breast cancer associated immune check point molecules (i.e., PD-L1) and inflammation indicators (i.e., IL8), based on disease progression.
Methods
Three-dimensional (3D) spheroids of estrogen receptor negative (ER–) and estrogen receptor positive (ER+) primary cells from Caucasian breast cancer patients, along with control/healthy cells (ATCC, MD), were cultured in medium between weeks 1 and 5, and tested weekly for cell proliferation and cell cycle status by Guave–8HT® flow cytometry (Millipore, MA) using kit assays. Each week 3D spheroids were lysed, and cell lysate assayed for cellular inducible nitric-oxide synthase (NOS2) expression, PD-L1, and IL8 using respective ELISA kit assays (abcam, MA); and their nitric-oxide production as total nitrite was determined by calorimetric assay (Cayman Chemicals, IL). NOHA in each week 3D spheroid cell lysate and cultured medium were determined by our proprietary ELISA assay, with a lower limit of quantification set at 0.06nM. Statistical difference for this study was set at p<0.01.
Results
Our in vitro studies show a progressive increase of ≥1-fold in cellular NOS2, total nitrites, PD-L1 and IL8, along with progressive decrease in cellular and medium NOHA by ≥ 1-fold only with ER– 3D spheroid group (p < 0.01, Figure. 1). ER+ or control 3D spheroid groups remained unchanged for all 5-weeks of the study period and their tested conditions. In ER– 3D spheroid group, a weekly decrease in cellular and medium NOHA by ≥ 5.2 % and ≥ 7.3 % respectively, correlated with cellular increases in PD-L1 by ≥18.8%, and IL8 by ≥23.4%. ER– 3D spheroid group also showed weekly cellular gain of ≥ 6.1% in NOS2 expression and ≥16.7% for total nitrite.
Conclusion
The present study provides first evidence for the strict association of NOHA with inflammation and immune-checkpoint molecules only under ER– distinctive breast cancer condition, and their disease progression. This work offers vital foundational knowledge for future delineation of NOHA metabolic impact in ER– breast cancer and associated phenotypic cellular modifications.
Poster 14
Exploring the Potential of Polyvinyl Acetate and PVP-90 to Prevent Alcohol Dose Dumping (ADD) and Considerations for Regulatory Guidance(s)
Ming Ji, Nitin Kumar Swarnakar, Sandip Tiwari
BASF Corporation
Presenting Author: Ming Ji, [email protected]
Corresponding Author: Nitin Kumar Swarnakar, [email protected]
Purpose
For this study, caffeine-containing modified release (MR) tablets were optimized using polyvinylpyrrolidone (PVP-90; Kollidon® K90 Evo) and a polyvinyl acetate (PVAc) dispersion (Kollicoat® SR 30D), along with PVP-90 in tablet core as pore former to mitigate alcohol dose dumping (ADD) risk. The stability of the formulation was investigated under accelerated storage conditions (40 °C and 75% relative humidity, RH). Additionally, the study discusses regulatory considerations for addressing the issue of ADD.
Methods
PVAc dispersion was mixed with various polymeric excipients/compositions. The swelling of the casted and dried polymer film was observed in 0.1N HCl and ethanol/0.1N HCl solution.
The PVAc coated caffeine tablets were stored in a HDPE bottle (induction sealed) with desiccant. Dissolution experiments were performed following the USP apparatus II method. The modified release films were characterized using texture analyzer.
Results
The film containing PVAc with PVP-90 demonstrated less swelling and better integrity in 0.1N HCl with alcohol.
The MR properties of the model caffeine tablets were maintained as suggested by FDA guidance in 40% alcoholic media, indicating no ADD effect. After changing the media to phosphate buffer (pH 6.8), the API release 100% within 5 h, much faster than the rate in 0.1N HCl with no alcohol. Under the alcoholic condition, the film exhibited lower tensile strength and was easier to break. This shows that MR tablet, which may meet the guidance requirement set by the FDA, could still pose a risk of burst release once the alcohol is removed from the test method.
Conclusion
This study demonstrated the effectiveness of incorporating polyvinyl acetate dispersion with PVP-90, along with PVP-90 in tablet core to address ADD risk. Although the formulation complies with regulatory requirement of the FDA, the impact of alcohol on the film characteristics compromises its mechanical strength, leading to faster release in non-alcoholic media. This raises concerns about the adequacy of current the FDA requirements for preventing ADD. The discrepancies between the ADD requirements of the EMA and the FDA can pose challenges for formulators as well. A harmonized recommendation from regulatory agencies is needed to establish a physiologically relevant in vitro methodology for assessing ADD.
Poster 15
ZoomLab-Enabled Design & Development of Rapidly Disintegrating Loratadine Tablets
Sravani Reddy, Nitin Kumar Swarnakar, Vivek Gupta
Sr. John's University
Presenting Author: Sravani Reddy, [email protected]
Corresponding Author: Vivek Gupta, [email protected]
Purpose
Loratadine, a piperidine derivative, is a long-acting, tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity. It is commonly used to treat allergy symptoms such as runny nose, itchy or watery eyes, sneezing, nasal or throat irritation, and chronic urticaria. In such severe allergic reactions, rapid commencement of action is critical. In the present study, we aim to develop rapidly disintegrating Loratadine tablets, using ZoomLab®, a digital product formulation development platform.
Methods
ZoomLab® (version 4.4) (a trademark of BASF SE) was used to develop Loratadine tablets, containing 10 mg of the API and a tablet weight of 100 mg. The input parameters related to API and dosage form such as dosage form class, administration route, dosage form, release kinetics, category of dosage form, dose of active ingredient, preferred tablet weight, tensile strength of tablets, melting point, glass transition temperature, etc., were added. Based on the input information, the software scans the physicochemical properties against Lipinski’s “Rule of Five” and categorizes it into appropriate BCS classes.
Based on the drug’s properties, ZoomLab® predicted a wet granulation approach to prepare these tablets, with the excipients – Avicel PH 102 (diluent), Kollidon CL-SF (super disintegrant), and sodium stearyl fumarate (lubricant). A carver hand press was used to compress the tablets with a compression pressure of 3500–4000 lbs, using a 5mm cup-shaped punch. Physicochemical characterization of Loratadine tablets included content uniformity, dissolution, thickness, hardness, DSC, and XRD.
Results
The DSC and XRD revealed that there was no drug-excipient interaction. The content uniformity results showed a uniform distribution of Loratadine with 96.7±7.3% drug content from the samples collected from different blend positions (top, bottom, left, right, up, and down). The dissolution studies revealed 100% drug release (103.8±1.5%) within 15 min in 0.1N hydrochloric acid, suggesting rapid disintegration, followed by the dissolution of the tablets. The thickness of the tablets was found to be 2.8±0.1 mm.
Conclusion
This study presents an excellent example of ZoomLab®-enabled product development as demonstrated by the successful development of rapidly disintegrating loratadine tablets. ZoomLab® accurately predicted excipients, ratios, and formulation parameters, thus eliminating the need for pre-formulation trials that may take years to complete. Further studies will focus on establishing ZoomLab® as an integral formulation development tool.
Poster 16
Repurposing the Unchained Labs Hound particle characterization instrument to maximize understanding of solid form during small molecule preclinical development
Robert Ozburn
Pfizer Inc.
Presenting Author: Robert Ozburn, [email protected]
Purpose
Preclinical formulators are routinely tasked with developing novel formulations, intended for animal dosing, using early discovery lots of active pharmaceutical ingredients (APIs). Oftentimes, these lots are less than 20mgs total and may contain metastable solid forms, amorphous/crystalline mixtures, or mixtures of different polymorphs. Since different solid forms of an API can exhibit differences in solubility, stability, and bioavailability, it is critical to keep track of solid forms of each lot throughout preclinical development, and to do so using material-sparing experimental techniques due to the small lot sizes. This poster showcases the repurposing of the Unchained Labs Hound particle characterization instrument to impact formulation and solid form identification/tracking in the early research space. Several cases studies will be presented to demonstrate its utility and advantages over traditional solid form characterization techniques, such as PXRD spectroscopy.
Methods
Raman Spectroscopy was conducted using Unchained Labs Hound instrument. This instrument is equipped with a 70mW 785nm laser and a 30mW 532nm laser. The objective used for Raman Spectroscopy is 50x, 0.5 NA, and 10.6mm WD. The spectral range is 200-3300 cm-1 with 6-10cm-1 resolution.
A small amount of sample (<0.5mg) was transferred to a gold-plated slide. Each sample was analyzed using a laser wavelength of 785nm, laser acquisition time of 5 seconds, and laser intensity of 100%. 20 Raman scans of each individual samples were collected and used to create an averaged reference spectrum. Prior to each experiment, an Acetylsalicylic Acid standard provided by Unchained Labs was used to ensure instrument function.
Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set at 11 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.1 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. In addition, the energy dispersive detector, a nickel filter was used to screen out unwanted wavelengths. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.02 degrees and a step time of 0.15 second. The antiscatter screen was set to a fixed distance of 1.5 mm. Samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.
Results
Pharmaceutical compounds with multiple well documented solid forms were examined using Raman Spectroscopy via the Unchained Labs Hound Instrument in a material sparing manner, with Powder X-Ray Diffraction and Polarized Light Microscopy used as orthogonal analytical methods. Raman spectra corresponding to different solid forms of the same compound collected using the Hound featured multiple new peak formations/wavenumber peak shifts, while using <0.5mg of material. The numerous spectra collected for each individual sample were used to create a reference spectrum for individual solid forms.
Mixtures of different solids forms of the same compound were examined using Raman Spectroscopy via the Unchained Labs Hound instrument in a material sparing manner. Using the Hound's point-and-shoot Raman technique, particles with different particle morphologies within the mixture were identified and analyzed using Hound Raman, with the resulting Raman spectra matching with the corresponding solid form.
Conclusion
The Raman capability of the Unchained Labs Hound instrument was able to effectively identify different solid forms of the same API and differentiate between different solid forms in mixtures while using a very small sample size (<0.5mg). This demonstrates the applicability of this instrument and Raman instruments alike in the preclinical space, when metastable forms are common and material sparing experimental techniques are essential.
Poster 17
Dissolution Method Design Based Upon Molecule PhysChem Properties and Human Gastroinstestinal Physiology
Joseph Middleton, Rohit Jaini, Brandon Tonthat, Lisa Belliveau, Priyanka Thipsay, Naimah Majeed, Patrick Dente
Pfizer Inc.
Presenting Author: Joseph Middleton, [email protected]
Purpose
When developing solid oral dosage forms, dissolution in biorelevant conditions is an important in-vitro test utilized to understand of the impact of dissolution on oral absorption. Of particular interest is the in-vitro performance of weakly-basic molecules possessing low solubility. To successfully accomplish this, a deep understanding of the intersection of human GI physiology, physicochemical properties of the molecule, and formulation characteristics must be employed. For example, a dibasic molecule recently in development was shown to interact with a range of common ions in solution and exhibited a complex pH solubility relationship. Because of this, it was important to understand what interactions are relevant in-vivo. These learnings were utilized to develop a discriminating biorelevant dissolution method with the goal of optimizing the bioperformance of an immediate release tablet.
Methods
Several compositions of dissolution media were proposed mimicking the different sections and states of the human gastrointestinal tract. These included conditions of the stomach in the fasted state both with and without a proton pump inhibitor in addition to the fasted and fed state small intestine. Dissolution media was designed to focus on physiologically relevant interactions that may exist in-vivo by including relevant concentrations of bile salts and sodium chloride. With these, dissolution testing was conducted in non-sink conditions in a USP-II apparatus utilizing fiber-optic in-situ UV-Vis spectrophotometry for detection.
Results
Dissolution results showed that formulations with lower drug loading dissolved more rapidly, completely, and reproducibly. Furthermore, the amount of disintegrant added to the formulation as well as the location (intragranular and extragranular) was found to be an important formulation attribute to optimize drug product design.
Conclusion
While dissolution in simulated gastric media was rapid and complete, the method did not provide the appropriate discriminatory power to assess performance. A method was developed utilizing and understanding of gastrointestinal conditions where most absorption occurs, and the solubility of basic drugs decreases for basic drugs. This allowed the development of a discriminating method to aid a rational drug product design and enabled nomination of a clinical formulation that has an increased probability of success.
Poster 9
Accelerated Stability Assessment Program (ASAP) Study of Peroxides in Excipients
Ridhima Shrestha, Jesse D. Scalesi, Louis Somma, Maria J. Krisch, and Kenneth C. Waterman
FreeThink Technologies, Inc.
Presenting Authors: Jesse D. Scalesi and Louis Somma, [email protected] and [email protected]
Corresponding Author: Maria J. Krisch, [email protected]
Purpose
Peroxides contribute to oxidative degradant formation in many pharmaceutical products. Peroxides can be introduced into pharmaceutical formulations as excipient process impurities, by peroxides that grow during excipient storage, and in the drug products themselves during shelf life. This study generates a predictive model for peroxides in several common excipients through a systematic understanding of the temperature and humidity dependence of this behavior.
Methods
Four different excipients—HPMCAS, HPC, and two types of povidones (Kollidon® 30, and Plasdone™ K-29/32)—were placed into canning jars and exposed to constant temperature and relative humidity stress conditions for up to 21 days. Stress conditions ranged from 60–90°C and 3–28% relative humidity, controlled by saturated salt solutions. Selected samples were stressed in parallel at low oxygen conditions. Peroxide growth was measured through the FOX2 peroxide assay using calibrated visible absorbance at 560 nm. The data are expressed in ppm, assuming that all peroxides measured are hydrogen peroxide.
Results
Peroxide growth in HPMCAS, Kollidon® 30, and Plasdone™ K-29/32 is well fit by a moisture-modified Arrhenius equation with average temperature dependences (Ea of 23–25 kcal/mol). All peroxides tested show a negative dependence on relative humidity, likely due to secondary degradation. Kollidon® 30 and Plasdone™ K-29/32 show the fastest peroxide growth as compared to HPC and HPMCAS. As expected, in the absence of oxygen, growth of peroxides with all excipients is repressed.
Conclusion
A model is demonstrated to quantify the temperature and relative humidity dependence of peroxide growth for four excipients. In contrast to the stability behavior of most materials, peroxide accumulation will be more significant under drier conditions.
Poster 10
Innovative Thermosensitive Hydrogel for Probiotic Delivery in Reproductive Tract Diseases: Enhancing Stability and Antibacterial Efficacy
Feng Zhou and Jiantao Zhang
Chinese Academy of Sciences
Presenting and Corresponding Author: Jiantao Zhang, [email protected]
Purpose
Bacterial reproductive tract diseases, caused by microbiota imbalances, lead to inflammation and complications such as preterm birth. Traditional probiotic delivery methods face challenges with adhesion, stability, and patient comfort. We developed a novel dual-chamber syringe system that separately stores liquid and solid probiotic formulations, mixing them just before use to form a water-based hydrogel. This in situ formation preserves probiotic viability, extends shelf life, and enhances therapeutic efficacy, offering a promising solution for restoring microbial balance and treating reproductive tract infections.
Methods
The liquid formulation was prepared by dissolving Poloxamer 407 in deionized water at various concentrations (15–24 wt%) and refrigerating overnight. Probiotic strains (Lactobacillus paracasei, Lactobacillus rhamnosus, and Bifidobacterium infantis) were cultured in MRS broth, incubated, and centrifuged to obtain bacterial pellets.
For solid formulations, probiotic pellets were mixed with excipients (maltodextrin, trehalose, sodium alginate, fumed silica, and inulin) under nitrogen. Alternative formulations involved mixing probiotics with inulin, maltodextrin, trehalose, and skim milk powder, followed by freeze-drying and milling. A dual-chamber syringe was used to combine the liquid and solid formulations, forming a probiotic-loaded hydrogel upon compression.
Results
The probiotic gel exhibited excellent batch-to-batch uniformity, maintaining activity for at least six months, whereas pure probiotic powder lost over 90% viability in two weeks. Antibacterial assays showed over 95% inhibition against four pathogens after six months of storage. Inhibition zone assays confirmed strong antibacterial efficacy, with active probiotic gels forming larger, clearer inhibition zones than inactivated gels. The gel technology was successfully applied to Lactobacillus rhamnosus and Bifidobacterium infantis, which maintained high viability for two months at 4°C and nearly 100% inhibition against Escherichia coli, Staphylococcus aureus, Candida albicans, and Gardnerella. Switching from a V-type mixer to an encapsulation mixing method improved uniformity.
Conclusion
Our dual-chamber syringe system enables in situ probiotic gel formation, ensuring long-term stability and high antibacterial efficacy, making it a promising platform for treating bacterial reproductive tract diseases.
Poster 11
Influence of Terminal Groups on PLGA Degradation and Their Role in the Sustained Release of Cyproterone Acetate
Qien Zhao, Junhui Yang, Jialin Liu, Shengyu Zhang, Wei Zhaob, Wenting Jiang, Hongxuan Yang, Yang Zhou, Lei Jiang, Jiantao Zhang
Chinese Academy of Sciences
Presenting and Corresponding Author: Jiantao Zhang, [email protected]
Purpose
This study aims to synthesize poly(lactic-co-glycolic acid) (PLGA) with varying terminal groups and bridge the knowledge gap on how the carbon chain length of these groups influences the degradation rates and drug release profiles of PLGA microspheres
Methods
In this study, four distinct PLGA polymers with different terminal groups (acid, n-hexanol, dodecanol, and hexadecanol) were synthesized, each with a molecular weight (Mw) of approximately 15,000, a lactic acid/glycolic acid (L/G) ratio of 74/26, and an inherent viscosity of 0.19 dL/g. A novel terminal group analysis method was developed to precisely characterize terminal group properties in PLGA, representing a significant advancement over traditional methods. Microspheres were prepared using the conventional oil-in-water (O/W) emulsion solvent evaporation method, in which a dichloromethane solution containing PLGA and cyproterone acetate (CYA) was injected into an aqueous polyvinyl alcohol solution to form an O/W emulsion. The study examined the impact of terminal group modifications on the degradation kinetics and drug release behavior of CYA-loaded microspheres, which were further characterized for volume mean diameter, drug loading rate, and encapsulation efficiency.
Results
The values for Mw, PDI, and inherent viscosity were found to be similar across all four PLGAs. The microspheres exhibited a volume mean diameter of 9 to 11 µm, a drug loading rate of approximately 10%, and an encapsulation efficiency of about 97%. The study demonstrated that terminal group length plays a crucial role in modulating the drug release profile, with the time to 50% release following this order: acid (~8 days) < n-hexanol (~9 days) < dodecanol (~14 days) < hexadecanol (~29 days). These findings underscore the significant impact of terminal group modifications on the degradation and drug release behavior of PLGA microspheres.
Conclusion
This study provides valuable insights into how variations in PLGA terminal groups can be leveraged to optimize drug release mechanisms, contributing to the development of advanced pharmaceutical excipients. The novel terminal group analysis method introduced here serves as a crucial tool for future research on PLGA modifications, enhancing the predictability and control of drug release in PLGA-based systems. These findings are expected to have a significant impact on the design of long-acting injectable formulations and other controlled-release applications.
Poster 12
Non-gelatin Film Coatings for Formulating Easy-to-Swallow Tablets
Kun Chen, Ming Ji, Nitin Kumar Swarnakar, Ashish Ashok Joshi, and Sandip Tiwari
BASF Corporation
Presenting Author: Kun Chen, [email protected]
Corresponding Author: Nitin Kumar Swarnakar, [email protected]
Purpose
A survey of literature shows that up to 40% of the general population has trouble swallowing medicines [1]. Gelatin-based tablet coatings facilitate ease of swallowing; however, they could cause stomach upset, heartburn, allergies, and possibly interaction with the active pharmaceutical ingredient (API) [2]. The animal origin of gelatin results in variability in molecular weight, bloom strength, and functional properties as well as raising BSE/TSE concerns[3]. Aqueous solutions of gelatin are not easy to handle due to the foaming and may result in stability issues for water- or oxygen-sensitive APIs. This study focuses on the use of compendial Kollicoat® IR (PEG-PVA graft copolymer - USP, EP) and Kollicoat® Protect (Kollicoat® IR + PVA), polymeric coating as effective alternatives to gelatin-based coating in formulating “easy-to-swallow” tablets. Additionally, such non-gelatin coatings offer good oxygen and moisture barrier properties without the risk of development of peroxides during storage.
Methods
Core tablet(s) (680 mg) consisting of 250 mg acetaminophen, 250 mg aspirin, 65 mg caffeine, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate, were manufactured by granulation followed by lubrication and compression. They were seal coated using PEG-PVA graft copolymer and PVA (6:4) (3% weight gain) followed by second layer of PEG-PVA graft copolymer (5% weight gain), both at 60 °C inlet temperature. Tablet slip performance, which evaluates ease of swallowing, was characterized using the method derived from static and dynamic friction test [4]. Each tablet was dipped into water for 1sec and placed on a Formica® laminated flat surface at different slope angles to evaluate the distance that each tablet slides down on the surface (Figure 3). Water vapor transmission rate (WVTR) and oxygen gas transmission rate (OGTR) were determined using isolated films of comparable thicknesses (70–75 μm), prepared using a Coatmaster™. To prevent sedimentation during the drying phase, the dispersions were cast in 3-4 thin layers (one on top of the other) depending on the pigment content and the film density.
The WVTR of PEG-PVA graft copolymer and PVA (6:4) was evaluated previously vs. PVA and HPMC using ASTM F 1249-20 [5] wherein a dry and wet chamber of known temperature and humidity are separated by the barrier film to be tested. Water vapor passing through the film mixes with gas in the dry chamber and is carried to a pressure modulated IR sensor, which generates an electrical signal proportional to the moisture content. The OGTR of PEG-PVA graft copolymer and PVA (6:4) and PEG-PVA graft copolymer were evaluated vs. PVA, HPC EF, and HPMC, using ASTM D 3985-17, in which the test sample is equilibrated in an environment with <1% relative humidity. The specimen is then mounted as a sealed semi-barrier between two chambers at ambient atmospheric pressure. One chamber is purged by a stream of nitrogen and the other chamber contains oxygen. As oxygen permeates through the film into the nitrogen carrier gas, it is transported to the coulometric detector where it produces an electrical current, the magnitude of which is proportional to the amount of oxygen flowing into the detector per unit time.
Results
PEG-PVA graft copolymer and PVA (6:4) seal-coating with high pigment concentration provides good moisture barrier properties, ideal for improving stability of moisture-sensitive APIs [6]. It can hold up to 75% pigment relative to the polymer, which is significantly higher than HPMC based coatings and easier to formulate than PVA based coatings. In addition, this coating exhibits excellent oxygen barrier properties. Tablets coated with PEG-PVA graft copolymer and PVA (6:4) alone showed improved slip performance vs. uncoated tablets which didn’t slide at a slope of 45o or lower. However, it was not equivalent to the marketed gelatin-coated tablet, possibly due to friction generated by talc present in the PEG-PVA graft copolymer and PVA (6:4) coating. To further improve the slip performance, a second coating layer of PEG-PVA graft copolymer was applied over the PEG-PVA graft copolymer and PVA (6:4) coated tablets. PEG-PVA graft copolymer is a water-soluble film former for instant release coatings. It is an excellent wet binder, and easily processed due to low solution viscosity (260 mPas of 25% solution), and very fast dissolution. When stored over 18 months under accelerated stability storage conditions, this polymer did not generate any peroxides (Data not shown). The two-layer coated tablets showed improved slip performance (slope as low as 15o) compared to gelatin coated marketed tablets. The minimum sliding force for the two-layer coated tablet is also lower than that of gelatin-coated market standard.
Conclusion
Gelatin-based tablet coatings use complicated manufacturing process and present issues with handling, stability, and consumer acceptance. The proposed dual-layer coated tablets (copolymer of PEG-PVA graft copolymer and PVA (6:4) followed by PEG-PVA graft copolymer) may serves as an improved non-gelatin alternative for greater ease of swallowing. Additionally, it offers better moisture protection in contrast to a standard film-coating. Further studies in clinical set up will help confirm the ease of swallowing and patient compliance.
Poster 13
Validating metabolic relevance of Nw-hydroxy L-Arginine to inflammatory and immune-checkpoint molecules based on breast cancer estrogen-receptor status
William Speltz, Megan Steele, Connor LaBonte, and Srinidi Mohan
University of New England
Presenting and Corresponding Author: Srinidi Mohan, [email protected]
Purpose
We have previously delineated Nw-hydroxy L-Arginine, (NOHA) as a predictive biomarker in distinguishing breast cancer based on estrogen-hormone-receptor status (USPTO 10,073,099), and on its utility with disease screening, as well as with high-risk breast cancer treatment response and therapy monitoring. In this study, we compare NOHA response with estrogen-receptor status selective breast cancer associated immune check point molecules (i.e., PD-L1) and inflammation indicators (i.e., IL8), based on disease progression.
Methods
Three-dimensional (3D) spheroids of estrogen receptor negative (ER–) and estrogen receptor positive (ER+) primary cells from Caucasian breast cancer patients, along with control/healthy cells (ATCC, MD), were cultured in medium between weeks 1 and 5, and tested weekly for cell proliferation and cell cycle status by Guave–8HT® flow cytometry (Millipore, MA) using kit assays. Each week 3D spheroids were lysed, and cell lysate assayed for cellular inducible nitric-oxide synthase (NOS2) expression, PD-L1, and IL8 using respective ELISA kit assays (abcam, MA); and their nitric-oxide production as total nitrite was determined by calorimetric assay (Cayman Chemicals, IL). NOHA in each week 3D spheroid cell lysate and cultured medium were determined by our proprietary ELISA assay, with a lower limit of quantification set at 0.06nM. Statistical difference for this study was set at p<0.01.
Results
Our in vitro studies show a progressive increase of ≥1-fold in cellular NOS2, total nitrites, PD-L1 and IL8, along with progressive decrease in cellular and medium NOHA by ≥ 1-fold only with ER– 3D spheroid group (p < 0.01, Figure. 1). ER+ or control 3D spheroid groups remained unchanged for all 5-weeks of the study period and their tested conditions. In ER– 3D spheroid group, a weekly decrease in cellular and medium NOHA by ≥ 5.2 % and ≥ 7.3 % respectively, correlated with cellular increases in PD-L1 by ≥18.8%, and IL8 by ≥23.4%. ER– 3D spheroid group also showed weekly cellular gain of ≥ 6.1% in NOS2 expression and ≥16.7% for total nitrite.
Conclusion
The present study provides first evidence for the strict association of NOHA with inflammation and immune-checkpoint molecules only under ER– distinctive breast cancer condition, and their disease progression. This work offers vital foundational knowledge for future delineation of NOHA metabolic impact in ER– breast cancer and associated phenotypic cellular modifications.
Poster 14
Exploring the Potential of Polyvinyl Acetate and PVP-90 to Prevent Alcohol Dose Dumping (ADD) and Considerations for Regulatory Guidance(s)
Ming Ji, Nitin Kumar Swarnakar, Sandip Tiwari
BASF Corporation
Presenting Author: Ming Ji, [email protected]
Corresponding Author: Nitin Kumar Swarnakar, [email protected]
Purpose
For this study, caffeine-containing modified release (MR) tablets were optimized using polyvinylpyrrolidone (PVP-90; Kollidon® K90 Evo) and a polyvinyl acetate (PVAc) dispersion (Kollicoat® SR 30D), along with PVP-90 in tablet core as pore former to mitigate alcohol dose dumping (ADD) risk. The stability of the formulation was investigated under accelerated storage conditions (40 °C and 75% relative humidity, RH). Additionally, the study discusses regulatory considerations for addressing the issue of ADD.
Methods
PVAc dispersion was mixed with various polymeric excipients/compositions. The swelling of the casted and dried polymer film was observed in 0.1N HCl and ethanol/0.1N HCl solution.
The PVAc coated caffeine tablets were stored in a HDPE bottle (induction sealed) with desiccant. Dissolution experiments were performed following the USP apparatus II method. The modified release films were characterized using texture analyzer.
Results
The film containing PVAc with PVP-90 demonstrated less swelling and better integrity in 0.1N HCl with alcohol.
The MR properties of the model caffeine tablets were maintained as suggested by FDA guidance in 40% alcoholic media, indicating no ADD effect. After changing the media to phosphate buffer (pH 6.8), the API release 100% within 5 h, much faster than the rate in 0.1N HCl with no alcohol. Under the alcoholic condition, the film exhibited lower tensile strength and was easier to break. This shows that MR tablet, which may meet the guidance requirement set by the FDA, could still pose a risk of burst release once the alcohol is removed from the test method.
Conclusion
This study demonstrated the effectiveness of incorporating polyvinyl acetate dispersion with PVP-90, along with PVP-90 in tablet core to address ADD risk. Although the formulation complies with regulatory requirement of the FDA, the impact of alcohol on the film characteristics compromises its mechanical strength, leading to faster release in non-alcoholic media. This raises concerns about the adequacy of current the FDA requirements for preventing ADD. The discrepancies between the ADD requirements of the EMA and the FDA can pose challenges for formulators as well. A harmonized recommendation from regulatory agencies is needed to establish a physiologically relevant in vitro methodology for assessing ADD.
Poster 15
ZoomLab-Enabled Design & Development of Rapidly Disintegrating Loratadine Tablets
Sravani Reddy, Nitin Kumar Swarnakar, Vivek Gupta
Sr. John's University
Presenting Author: Sravani Reddy, [email protected]
Corresponding Author: Vivek Gupta, [email protected]
Purpose
Loratadine, a piperidine derivative, is a long-acting, tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity. It is commonly used to treat allergy symptoms such as runny nose, itchy or watery eyes, sneezing, nasal or throat irritation, and chronic urticaria. In such severe allergic reactions, rapid commencement of action is critical. In the present study, we aim to develop rapidly disintegrating Loratadine tablets, using ZoomLab®, a digital product formulation development platform.
Methods
ZoomLab® (version 4.4) (a trademark of BASF SE) was used to develop Loratadine tablets, containing 10 mg of the API and a tablet weight of 100 mg. The input parameters related to API and dosage form such as dosage form class, administration route, dosage form, release kinetics, category of dosage form, dose of active ingredient, preferred tablet weight, tensile strength of tablets, melting point, glass transition temperature, etc., were added. Based on the input information, the software scans the physicochemical properties against Lipinski’s “Rule of Five” and categorizes it into appropriate BCS classes.
Based on the drug’s properties, ZoomLab® predicted a wet granulation approach to prepare these tablets, with the excipients – Avicel PH 102 (diluent), Kollidon CL-SF (super disintegrant), and sodium stearyl fumarate (lubricant). A carver hand press was used to compress the tablets with a compression pressure of 3500–4000 lbs, using a 5mm cup-shaped punch. Physicochemical characterization of Loratadine tablets included content uniformity, dissolution, thickness, hardness, DSC, and XRD.
Results
The DSC and XRD revealed that there was no drug-excipient interaction. The content uniformity results showed a uniform distribution of Loratadine with 96.7±7.3% drug content from the samples collected from different blend positions (top, bottom, left, right, up, and down). The dissolution studies revealed 100% drug release (103.8±1.5%) within 15 min in 0.1N hydrochloric acid, suggesting rapid disintegration, followed by the dissolution of the tablets. The thickness of the tablets was found to be 2.8±0.1 mm.
Conclusion
This study presents an excellent example of ZoomLab®-enabled product development as demonstrated by the successful development of rapidly disintegrating loratadine tablets. ZoomLab® accurately predicted excipients, ratios, and formulation parameters, thus eliminating the need for pre-formulation trials that may take years to complete. Further studies will focus on establishing ZoomLab® as an integral formulation development tool.
Poster 16
Repurposing the Unchained Labs Hound particle characterization instrument to maximize understanding of solid form during small molecule preclinical development
Robert Ozburn
Pfizer Inc.
Presenting Author: Robert Ozburn, [email protected]
Purpose
Preclinical formulators are routinely tasked with developing novel formulations, intended for animal dosing, using early discovery lots of active pharmaceutical ingredients (APIs). Oftentimes, these lots are less than 20mgs total and may contain metastable solid forms, amorphous/crystalline mixtures, or mixtures of different polymorphs. Since different solid forms of an API can exhibit differences in solubility, stability, and bioavailability, it is critical to keep track of solid forms of each lot throughout preclinical development, and to do so using material-sparing experimental techniques due to the small lot sizes. This poster showcases the repurposing of the Unchained Labs Hound particle characterization instrument to impact formulation and solid form identification/tracking in the early research space. Several cases studies will be presented to demonstrate its utility and advantages over traditional solid form characterization techniques, such as PXRD spectroscopy.
Methods
Raman Spectroscopy was conducted using Unchained Labs Hound instrument. This instrument is equipped with a 70mW 785nm laser and a 30mW 532nm laser. The objective used for Raman Spectroscopy is 50x, 0.5 NA, and 10.6mm WD. The spectral range is 200-3300 cm-1 with 6-10cm-1 resolution.
A small amount of sample (<0.5mg) was transferred to a gold-plated slide. Each sample was analyzed using a laser wavelength of 785nm, laser acquisition time of 5 seconds, and laser intensity of 100%. 20 Raman scans of each individual samples were collected and used to create an averaged reference spectrum. Prior to each experiment, an Acetylsalicylic Acid standard provided by Unchained Labs was used to ensure instrument function.
Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set at 11 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.1 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. In addition, the energy dispersive detector, a nickel filter was used to screen out unwanted wavelengths. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.02 degrees and a step time of 0.15 second. The antiscatter screen was set to a fixed distance of 1.5 mm. Samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.
Results
Pharmaceutical compounds with multiple well documented solid forms were examined using Raman Spectroscopy via the Unchained Labs Hound Instrument in a material sparing manner, with Powder X-Ray Diffraction and Polarized Light Microscopy used as orthogonal analytical methods. Raman spectra corresponding to different solid forms of the same compound collected using the Hound featured multiple new peak formations/wavenumber peak shifts, while using <0.5mg of material. The numerous spectra collected for each individual sample were used to create a reference spectrum for individual solid forms.
Mixtures of different solids forms of the same compound were examined using Raman Spectroscopy via the Unchained Labs Hound instrument in a material sparing manner. Using the Hound's point-and-shoot Raman technique, particles with different particle morphologies within the mixture were identified and analyzed using Hound Raman, with the resulting Raman spectra matching with the corresponding solid form.
Conclusion
The Raman capability of the Unchained Labs Hound instrument was able to effectively identify different solid forms of the same API and differentiate between different solid forms in mixtures while using a very small sample size (<0.5mg). This demonstrates the applicability of this instrument and Raman instruments alike in the preclinical space, when metastable forms are common and material sparing experimental techniques are essential.
Poster 17
Dissolution Method Design Based Upon Molecule PhysChem Properties and Human Gastroinstestinal Physiology
Joseph Middleton, Rohit Jaini, Brandon Tonthat, Lisa Belliveau, Priyanka Thipsay, Naimah Majeed, Patrick Dente
Pfizer Inc.
Presenting Author: Joseph Middleton, [email protected]
Purpose
When developing solid oral dosage forms, dissolution in biorelevant conditions is an important in-vitro test utilized to understand of the impact of dissolution on oral absorption. Of particular interest is the in-vitro performance of weakly-basic molecules possessing low solubility. To successfully accomplish this, a deep understanding of the intersection of human GI physiology, physicochemical properties of the molecule, and formulation characteristics must be employed. For example, a dibasic molecule recently in development was shown to interact with a range of common ions in solution and exhibited a complex pH solubility relationship. Because of this, it was important to understand what interactions are relevant in-vivo. These learnings were utilized to develop a discriminating biorelevant dissolution method with the goal of optimizing the bioperformance of an immediate release tablet.
Methods
Several compositions of dissolution media were proposed mimicking the different sections and states of the human gastrointestinal tract. These included conditions of the stomach in the fasted state both with and without a proton pump inhibitor in addition to the fasted and fed state small intestine. Dissolution media was designed to focus on physiologically relevant interactions that may exist in-vivo by including relevant concentrations of bile salts and sodium chloride. With these, dissolution testing was conducted in non-sink conditions in a USP-II apparatus utilizing fiber-optic in-situ UV-Vis spectrophotometry for detection.
Results
Dissolution results showed that formulations with lower drug loading dissolved more rapidly, completely, and reproducibly. Furthermore, the amount of disintegrant added to the formulation as well as the location (intragranular and extragranular) was found to be an important formulation attribute to optimize drug product design.
Conclusion
While dissolution in simulated gastric media was rapid and complete, the method did not provide the appropriate discriminatory power to assess performance. A method was developed utilizing and understanding of gastrointestinal conditions where most absorption occurs, and the solubility of basic drugs decreases for basic drugs. This allowed the development of a discriminating method to aid a rational drug product design and enabled nomination of a clinical formulation that has an increased probability of success.
