Improved Pharma Announces Pharmaceutical R&D Efforts in 2021

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Improved Pharma contributed to eight scientific publications on amorphous materials, formulation, quality, and solid-state screening

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This past year has been very exciting for the Improved Pharma team. We’re grateful to our collaborators for all they are doing to advance pharmaceutical development and are thrilled to be a part of these very important studies.

Developing new tools and advancing pharmaceutical development is a key part of Improved Pharma’s mission. In 2021, the results from several research and development projects were published with our team of consultants and collaborators. Most of the research focused on the development of amorphous materials and understanding their behavior in amorphous dispersion formulations. The next largest field of study that was published involved salt and polymorph screens of bedaquiline. Other publications focused on abuse-deterrent formulations and quality risk factors. In total, 8 studies enabling the advancement of several pharmaceutical products were published. The complete list is referenced below.

“This past year has been very exciting for the Improved Pharma team,” exclaims Dr. Stephen Byrn, CSO of Improved Pharma. “We’re grateful to our collaborators for all they are doing to advance pharmaceutical development and are thrilled to be a part of these very important studies.”

Publications on amorphous materials:

Acoustic levitation and high-resolution synchrotron X-ray powder diffraction: A fast screening approach of niclosamide amorphous solid dispersions
By Barbosa, Eduardo J.; Andrade, Marco A. B.; Gubitoso, Mariana R.; Bezzon, Vinicius D. N.; Smith, Pamela A.; Byrn, Stephen R.; Bou-Chacra, Nadia A.; Carvalho, Flavio M. S.; de Araujo, Gabriel L. B.
From International Journal of Pharmaceutics (Amsterdam, Netherlands) (2021), 602, 120611.
The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.

Amorphous dispersions of flubendazole in hydroxypropyl methylcellulose: Formulation stability assisted by pair distribution function analysis
By Bezzon, Vinicius D. N.; Ferreira, Fabio F.; Smith, Pamela; Benmore, Chris J.; Byrn, Stephen R.; de Araujo, Gabriel L. B.
From International Journal of Pharmaceutics (Amsterdam, Netherlands) (2021), 600, 120500.
We use X-ray pair distribution function (PDF) analysis applied to high-energy synchrotron X-ray powder diffraction data to evaluate the amorphous solid dispersions interactions and their aging stability. The obtained systems are based on hydroxypropyl methylcellulose (hypromellose) derivatives and flubendazole (FBZ) drug dispersions prepared using a spray-dryer technique. We carry out stability studies under aging parameters (40 °C/75% relative humidity) to tune the systems' recrystallization. The results reveal that ion-base interactions between the drug-polymer matrix are responsible for reducing clustering processes yielding slower recrystallization and different ordering in the hypromellose phthalate (HPMCP/FBZ) and hypromellose acetate succinate (HPMC-AS/FBZ) systems and complete drug clustering in hypromellose (HPMC-E3/FBZ). The structural ordering was accessed using differential X-ray PDFs that revealed the region between 3.5 Å and 5.0 Å could be related to FBZ intermolecular interactions and is more ordered for the least stable system (HPMC-E3/FBZ) and less ordered for the most stable system (HPMCP/FBZ). These results show that the ion-base interactions between drug and matrix occur at these intermolecular distances.

Development of a Pediatric Mini-Tablet Formulation for Expedited Preclinical Studies
By Lavan, Monika; Wang, Xueqi; McCain, Robyn; Jannasch, Amber; Cooper, Bruce; Hostetler, Scott; Byrn, Stephen; Knipp, Gregory
From AAPS PharmSciTech (2021), 22(1), 40.
Multiple considerations are essential to address the main challenges of dose flexibility and patient adherence in pediatric drug development, particularly for oncology. Mini-tablets, 2 mm in diameter, were manufactured using a rotary tablet press at a set weight and compression force level. The physical characteristics were consistent for mini-tablets throughout multiple batches. Polymeric amorphous solid dispersion (ASD) was used as a solubility enhancing technique to increase solubility and exposure of lapatinib. The effects of the polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellulose E3 (HPMCE3) formulation provided a higher percentage of drug release compared to hydroxypropyl methylcellulose phthalate (HPMCP). The intermolecular interaction within the ASD system plays a role in the level of apparent solubility, physical stability, and concentration of free drug available in an aqueous environment. Juvenile porcine models at two different weight groups (10 and 20 kg) were used to obtain the pharmacokinetic parameters of lapatinib. While the dose-normalized exposure of drug was found to be lower in the pig study, the dose flexibility of mini-tablets enabled a constant dose level to be administered to achieve equivalent plasma concentration-time profiles between the two groups. This linear scaling in the amount of drug in pediatric and adult population has also been observed in human clinical studies.

A high energy x-ray diffraction study of amorphous Indomethacin
By Benmore C J; Benmore S R; Weber J K R; Edwards A D; Shrader C D; Bhat M H; Cherry B R; Yarger J L; Smith P; Smith D; Gozzo F, Shi C, Byrn S R
From Journal of pharmaceutical sciences (2021).
Amorphous pharmaceuticals often possess a wide range of molecular conformations and bonding arrangements. The x-ray pair distribution function (PDF) method is a powerful technique for the characterization of variations in both intra-molecular and inter-molecular packing arrangements. Here, the x-ray PDF of amorphous Indomethacin is shown to be particularly sensitive to the preferred orientations of the chlorobenzyl ring found in isomers in the crystalline state. In some cases, the chlorobenzyl ring has no preferred torsional angle in the amorphous form, while in others evidence of distinct isomer orientations are observed. Amorphous samples with no preferred torsion angles of the chlorobenzyl ring are found to favor enhanced inter-molecular hydrogen bonding, and this is reflected in the intensity of the first sharp diffraction peak. These significant variations in structure rule out amorphous Indomethacin as a possible standard for x-ray PDF measurements. At high humidity, time resolved PDFs for >40 hours reveal water molecules forming hydrogen bonds with Indomethacin molecules. A simple linear hydrogen bond model indicates that water molecules in the wet amorphous form have similar hydrogen bond strengths to those found between Indomethacin dimers or chains in the dry amorphous form.

Publications on salt and polymorph screens:

Salts and Polymorph Screens for Bedaquiline
By Okezue, Mercy; Bogdanowich-Knipp, Susan; Smith, Daniel; Zeller, Matthias; Byrn, Stephen; Smith, Pamela; Purcell, Dale K.; Clase, Kari
From AAPS PharmSciTech (2021), 22(7), 228.
Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.

Maleate salts of bedaquiline
By Zeller, Matthias; Bogdanowich-Knipp, Susan; Smith, Pamela; Purcell, Dale K.; Okezue, Mercy; Smith, Daniel T.; Byrn, Stephen R.; Clase, Kari L.
From Acta Crystallographica, Section E: Crystallographic Communications (2021), 77(4), 433-445.
Bedaquiline is one of two important new drugs for the treatment of drug-resistant tuberculosis (TB). It is marketed in the US as its fumarate salt, but only a few salts of bedaquiline have been structurally described so far. We present here five crystal structures of bedaquilinium maleate {systematic name: [4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate}, C32H32BrN2O2+·C4H3O4-, namely, a hemihydrate, a THF (THF) solvate, a mixed acetone/hexane solvate, an Et acetate solvate, and a solvate-free structure obtained from the acetone/hexane solvate by in situ single-crystal-to-single-crystal desolvation. All salts exhibit a 1:1 cation-to-anion ratio, with the anion present as monoanionic hydromaleate and a singly protonated bedaquilinium cation. The maleate exhibits the strong intramol. hydrogen bond typical for cis-dicarboxylic acid anions. The conformations of the cations and packing interactions in the maleate salts are compared to those of free base bedaquiline and other bedaquilinium salts.

Publications on abuse deterrent formulations:

Evaluation of tableting performance of Poly (ethylene oxide) in abuse-deterrent formulations using compaction simulation studies
By Yu, Dongyue; Seelam, Raghunadha Reddy; Zhang, Feng; Byrn, Stephen R.; Hoag, Stephen W.
From Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2021), 110(7), 2789-2799.
Poly (ethylene oxide) (PEO) has been widely used in abuse-deterrent formulations (ADFs) to increase tablet hardness. Previous studies have shown that formulation variables such as processing conditions and particle size of PEO can affect ADF performance in drug extraction efficiency. This work aims to understand the effect of PEO grades and sources on the compaction characteristics of model ADFs. PEOs from Dow Chemical and Sumitomo Chemical with different molecular weights were examined using a Styl'One compaction simulator at slow, medium, and fast tableting speeds. Particle-size distribution, thermal behavior, tabletability, compressibility using the Heckel model, compactibility, and elastic recovery were determined and compared between the neat PEOs and model ADFs. Multivariate linear regression was performed to understand the effect of compression conditions and PEO grades and sources. Our results show that neat PEOs with high molecular weight exhibit high tabletability. The source of neat PEOs contributes to the difference in tabletability, out-die compressibility, compactibility, and elastic recovery. However, the influence of the PEO source on tabletability and compactibility decreases after adding the model drug. In our model ADFs, tablets using PEOs with high molecular weight have high crushing strength, and tablets using PEOs from Dow Chemical display low elastic recovery.

Publications on quality:

The Identification of Quality Risk Factors for Non-biological Complex Drugs and Epilepsy Drugs Using Statistical Analysis of Formulation-Based Recalls in the USA
By Kerstiens Emily A; Clase Kari L; Byrn Stephen R
From AAPS PharmSciTech (2021), 23(1), 19.
Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.

About Improved Pharma
Improved Pharma is a research, consulting, and information company dedicated to improving pharmaceutical methods, formulations, and processes. Services include solid-state form studies, formulation design, synchrotron techniques, analytical testing, and expert consulting for the development and defense of intellectual property matters. The company was founded in 2006 by Stephen and Sarah Byrn, who also founded SSCI.

For more information about the analytical technique discussed in this press release or about Improved Pharma’s services, please contact us at 1-765-463-9951 or info@improvedpharma.com.

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