Novel Co-processing Methodology to Enable Direct Compression of a

Subscriber access provided by University of South Dakota

Full Paper

Novel Co-processing Methodology to Enable Direct Compression of a Poorly Compressible Highly Water-Soluble API for Controlled Release Deniz Erdemir, Tamar Rosenbaum, Shih-Ying Chang, Benjamin Wong, Donald Kientzler, Steve Wang, Divyakant Desai, and San Kiang Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00204 • Publication Date (Web): 06 Sep 2018 Downloaded from http://pubs.acs.org on September 6, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Novel Co-processing Methodology to Enable Direct Compression of a Poorly Compressible Highly Water-Soluble API for Controlled Release Deniz Erdemir,* Tamar Rosenbaum, Shih-Ying Chang,† Benjamin Wong,‡, Donald Kientzler, Steve Wang, Divyakant Desai, and San Kiang§ Drug Product Science and Technology, Bristol Myers Squibb, 1 Squibb Drive, New Brunswick NJ 08903

ACS Paragon Plus Environment

1

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 33

Table of Contents graphic


2

Page 3 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


KEYWORDS: direct compression, co-processing, controlled release formulation, crystallization, tablet, API

ABSTRACT: Herein we introduce an innovative process for preparation of directly compressible API and excipient agglomerates for extended release formulation of a highly water soluble drug, demonstrated with metformin HCl. Metformin is poorly compressible and currently employs wet granulation for tablet manufacturing, resulting in long cycle times. We have co-processed metformin HCl with hydroxypropyl methylcellulose (HPMC) and sodium carboxymethlycellulose (NaCMC) in solvent medium to generate agglomerates which were tableted via direct compression, thereby reducing the drug product manufacturing cycle time and cost, while maintaining extended release dissolution profile. The intimate mixing of HPMC and NaCMC with metformin HCl through co-processing reduces the risk of segregation during downstream handling and tableting. Additionally, this process reduced the excipient load required to achieve the target dissolution profile and bioequivalence, leading to reduced tablet mass and size with 1000 mg drug load.


3


Page 4 of 33

INTRODUCTION Compressed tablets are the most widely used solid dosage form to date, due to ease of administration, greatest dose precision, least content variability, and suitability for large scale production.1 The most streamlined process to prepare tablets is direct compression of the active pharmaceutical ingredient (API) and excipient blend. However, some drugs may resist compression into tablet form because of poor physical properties, resulting in tablets that do not satisfy requirements such as hardness, uniformity, disintegration, and friability.2 Although compression into a tablet can be facilitated in these cases via preparation of granules of API and excipient via wet granulation, this carries potential liability if the API is sensitive to heat or moisture, and requires many more processing steps, increasing the cycle time.3,4 Thus, methodologies that allow for direct compression of challenging APIs provide significant advantages from both a stability perspective as well as a processing perspective. Most work to facilitate direct compression has focused on preparing excipients with enhanced powder properties to mask the poor properties of the API.3,5,6 Co-processed excipients, prepared via combining two or more excipients by an appropriate process, offer superior powder properties over a physical mixture of the components.2 For example, direct compression of acetaminophen with Cellactose, co-processed cellulose and lactose, resulted in tablets that met specifications.7 However, a limitation with co-processed excipients is that the ratio of excipients (e.g. cellulose:lactose ratio in the case of Cellactose) in the co-processed product is fixed, and may not be the optimum ratio for a given API.2 In addition, sometimes more than 40% of highly bonding excipients is required to attain sufficient powder tabletability, which leads to problems such as large tablet size and poor content uniformity.8 Over the last 20 years, this concept has been extended to the co-processing of APIs


4

Page 5 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


together with excipient(s) as an API particle engineering approach. The co-processing route for API is typically explored when the desired powder properties are difficult to achieve through conventional particle engineering approaches, such as particle size and habit modification during crystallization via solvent/antisolvent choice, supersaturation control, and seeding strategies,9 or more specialized techniques, such as spherical agglomeration by the use of bridging liquid.10-14 Co-processing techniques include co-spray drying,8,15 melt granulation,16 adsorption of drug in porous carrier,17 surface modification by dry coating,16,19 and controlled crystallization of API in presence of excipients in solvent media. Methodologies involving solvent media include morphology modification by via use of habit modifiers,20 crystallization on the surface of excipient through heteroepitaxial mechanism,21 and crystallo-co-agglomeration (CCA).22-26 Crystallo-co-agglomeration (CCA), a variation of the spherical crystallization technique wherein the drug is crystallized and agglomerated with an excipient or another drug, has been demonstrated on numerous drugs to improve compactability and allow for direct compression. However, the application of this technique has been limited to water-insoluble drugs. For drugs possessing very high water solubility and that require extended release formulation, large amounts of polymer are typically required in order to reduce the rate of drug release to an appropriate level consistent with the desired blood level profile.27 When this is coupled with high drug load and poor powder properties, direct compression of such blends can be extremely challenging. Therefore, to allow for direct compression of difficult-to-compress and highly water soluble API with high drug load, we have developed a methodology of co-processing an API together with the release modifying excipients, resulting in agglomerates of API and excipient which are suitable for direct compression, and which are capable of achieving an extended release dissolution profile.28 Metformin HCl was chosen as an API to showcase this


5


Page 6 of 33

methodology. Metformin is an antihyperglycemic agent marketed in hydrochloride salt form (HCl) under the trade name GLUCOPHAGE®. It has a high aqueous solubility of approximately 300 mg/mL in the pH range of 1.2–6.8 at 25 ºC.29 Due to low oral bioavailability and short variable biological half-life, an extended release formulation that allows for once-daily dosing is of clinical benefit.30,31 However, there exist significant manufacturing challenges with preparing a benchmark 1000 mg extended-release metformin HCl (Met XR) tablet. Metformin HCl is known to have poor compaction properties, making it difficult to form tablets by direct compression techniques.32 Therefore, wet granulation is employed commercially to obtain API/excipient agglomerates with suitable compression properties. Current wet granulation of metformin involves multiple and lengthy processing steps including blending of metformin HCl and sodium carboxymethlycellulose (NaCMC), high shear wet granulation, delumping, drying and milling of the granules. Hydroxypropyl methylcellulose (HPMC) K100M is subsequently added extra-granularly as a controlled release agent, prolonging the release of the drug due to high viscosity.27 The difference in bulk density of granules and HPMC K100M poses a risk of segregation and poor content uniformity. Although there has been work towards preparing directly compressed extended release metformin tablets, many formulations could not achieve 1000 mg drug loading,33, 34 complete drug dissolution,35 or extended release past 8 hours36. Other methodologies had the drawback of requiring specialized processing equipment for preparation.37, 16 In this paper, we describe a methodology that involves crystallization of metformin in a solvent environment in the presence of excipients. The process uses common crystallization vessels and agitated dryer, without the need for specialized equipment such as spray dryer or hot


6

Page 7 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


melt extruder. The process results in agglomerates composed of API and excipients which are readily amenable to direct compression, allowing for improved cycle time, and streamlining processing. In addition, due to the intimate mixing of the API and excipient within the agglomerate, the excipient load required to achieve the target dissolution profile was reduced, leading to reduced tablet mass and size with 1000 mg formulation. This co-processing methodology was successfully demonstrated in pilot scale and can be applicable to other difficult to compress highly water-soluble API with extended release formulation as well. EXPERIMENTAL Materials: Metformin HCl with 0.5 wt% magnesium stearate was supplied by Merck Serono (Merck Serono, Calais, France). Metformin HCl without magnesium stearate was supplied by Merck Sante (Merck Sante, Lyon, France). The following materials were used as received from the supplier: sodium carboxymethlycellulose (NaCMC) (Aqualon CMC, 7HF Grade) (Ashland, Hopewell, VA), hydroxypropyl methylcellulose NF (METHOCEL, K100M Grade) (Dow Chemical, Midland, MI), hydroxypropyl cellulose (HPC) NF (NISSO, H Grade) (Nippon Soda, Niigata Prefecture, Japan), HPC-HXF (Klucel®, Ashland, Wilmington, DE), magnesium stearate NF (Mallinckrodt, St. Louis, MO), acetone (Sigma Aldrich, St. Louis, MO), ethyl acetate (Sigma Aldrich, St. Louis, MO). Preparation of co-processed material: Commercially supplied metformin HCl, provided as white crystalline powder, was dissolved in water (2.8 L per kg of metformin HCl) to prepare a concentrated solution of 270 mg/mL. At this concentration, the metformin HCl solution was undersaturated. If the commercial metformin HCl contained magnesium stearate, the solution was polish filtered, since magnesium stearate does not dissolve in water. In a separate crystallization vessel, a solvent mixture of 57 vol% acetone and 43 vol% ethyl acetate


7


Page 8 of 33

was prepared. The total volume of the solvent mixture was 27.4 L per kg of metformin HCl input in the first step. The HPMC K100M and NaCMC were suspended in this solvent mixture at 20oC under high agitation. Next, the rich aqueous solution prepared in the first step was added into the polymer slurry over 2-3 hours while agitating vigorously, which resulted in crystallization of metformin HCl. Figure 1 illustrates the process for targeted co-processed material composition of 80 wt% metformin HCl, 16 wt% HPMC K100M and 4 wt% NaCMC. In the flow diagram, the solvent volumes (L/kg) are given with respect to the metformin HCl input to the process. This same process was conducted at the lab scale (~5 g API) all the way up to pilot plant scale (40 kg API).

Figure 1. Co-processing procedure for Met XR formulation.

The isolation protocol for co-processed material slurry is illustrated in Figure 2. The solvent volumes (L/kg) are given with respect to the metformin HCl input to the process. The slurry was first filtered and then deliquored. The cake was then washed with acetone containing 6 vol% water, followed by a re-slurry wash with the same solvent composition. The densification was achieved by agitating the wet cake in the filter dryer until cake height was constant. Next, the cake was dried at 60oC under vacuum with periodic agitation and then transferred from the dryer to a co-mill for delumping before packaging. For comparison, material from the crystallization was also tray dried via isolation on a Buchner funnel, followed by thoroughly


8

Page 9 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


washing with acetone and drying in a vacuum oven overnight at 60°C. The reported results in this manuscript correspond to materials densified and dried under agitation, unless otherwise stated.

Figure 2. Isolation procedure for co-processed Met XR formulation.

Tablet Compression: Co-processed material from plant batches (5 kg and 40 kg scale) was first passed through #30 mesh screen followed by a lubrication step with 0.5% w/w magnesium stearate in Octagonal blender (Gansons, Mumbai) Final blend was compressed using a rotary tablet press (CU-20, Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, India) tooled with capsule-shaped D tooling (19.8 x 10.2 mm). The blend was compressed to achieve a tablet hardness of about 40 SCU. The turret speed and force feeder were maintained at about 15-30 rpm and 30 rpm, respectively, during each compression run. The weight of the tablet was adjusted based on the potency of the co-processed intermediate. Tableting was closely monitored to ensure the targeted tablet weight and hardness were achieved. The final tablet weight was


9


Page 10 of 33

1256 mg ± 5%. Characterization: A variety of techniques were employed to characterize and evaluate the agglomerates and their performance. Reported typical values are from different 5 kg and 40 kg scale batches, to highlight the reproducibility and robustness of the process at production scale. Physical Properties: Optical microscope images (AxioScope A.1, Zeiss, Thornwood, NY) of the slurry were captured in order to follow the evolution of the size and morphology of the particles in a qualitative manner throughout the process. Scanning electron micrographs (SEM) (JSM-6510, Jeol, Peabody, MA) were collected to characterize the size and morphology of the dried agglomerates. Estimation of particle size distribution for co-processed material was performed by using test sieves of mesh ASTM #20, #40, #60 and #80. The sieves were stacked on top of one another in ascending degrees of coarseness, and then the test powder was placed on the top sieve. The sieves were subjected to electromagnetic agitation (i.e. power 15 vibration using electromagnetic sieve shaker) for a period of 10 minutes and then the weight of the material retained on each sieve was accurately determined. This test gives the weight percentage of granules in each sieve range. Powder X-ray diffraction (PXRD) spectra were collected on a bench-top XRD instrument (Miniflex, Rigaku, TX) to confirm the polymorphic form of coprocessed metformin HCl. Chemical Properties: Total residual solvents in the dried material were determined by loss on drying (LOD) method using Halogen moisture analyzer (Mettler Toledo, Greifensee, Switzerland) and percent of volatiles in the dried material were determined by gas chromatography. Potency testing of the material was conducted by dissolving metformin HCl co-processed material in a 100 mL volumetric flask containing diluent of 80% v/v water and


10

Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


20% v/v acetonitrile to a concentration of 0.3 mg/mL, sonicating for 5 min, and manually mixing. Sample solutions were filtered using 0.45 micron PVDF Acrodisc (Port Washington, NY) before injecting the clear solutions into the HPLC system. The HPLC conditions for the assay of metformin HCl include stationary phase, Water µ Bondapak C18, 300 mm x 3.9 mm i.d., 10 µm particle size; guard column, Water µ Bondapak C18, 300 mm x 3.9 mm i.d., 10 µm particle size; mobile phase, 90% v/v of 0.05% w/v Sodium salt of 1-hepatanesulfonic acid and 0.05% w/v Sodium chloride buffer, pH 3.85, 10% v/v acetonitrile; flow rate, 1.0 ml/min; UV detection wavelength, 218 nm; column temperature, 30°C; retention time, 7.6 min. Chemical mapping to determine agglomerate composition was conducted by Raman imaging with a DXR Raman Microscope (Thermo Scientific, Madison, WI) equipped with DXR 532 nm Laser and Olympus U-TV 0.5xC-3 microscope. Raman spectra of metformin HCl, HPMC K100M and the co-processed material were collected in the 50-3500 cm-1 range. The Raman mapping was performed with ~ 5 µm spatial resolution for the control sample, which was a physical mixture of 80% Metformin HCl, 16% HPMC K100M, and 4% Na CMC, and the coprocessed sample with similar composition. A high energy focused Ga ion beam (FIB) was used to etch away the upper portion of an individual agglomerate, thus creating a cross section. The cross section was then scanned via electron dispersive X-ray spectroscopy (EDS), an analytical technique which employs the interaction of X-rays with a material to chemically map the material. As the API is a hydrochloride salt, which is chemically distinct compared to the polymers, it allowed for identification of API regions within the agglomerate cross-section. Mechanical & Flow Properties: Bulk density of the co-processed agglomerates was measured by gently transferring the powder into a graduated cylinder and calculating the ratio of


11


Page 12 of 33

the mass of the powder to its volume. To test the strength of the agglomerates, granule integrity testing (GIT) was conducted. First, the co-processed material was manually sieved through 300, 600 and 1000 micron screens. The weight percentage of particles in each size range was determined. The material was subjected to low-frequency, high intensity acoustic energy (73G) that created a uniform shear field throughout the entire mixing vessel (LABRAM, Resodyne Acoustic Mixers, Butte, MT). Next, the sieve analysis was repeated to determine the weight percentage of particles in each size range after the application. The GIT index was calculated by taking the difference between the weight percentages of particles greater than 300 m before and after the exposure to high intensity resonant acoustic energy. The GIT index of 0 refers to complete integrity of granules (i.e. no attrition or breakage to smaller sizes), 0.6 refers to fragile granules and 1 refers to no granule integrity.38 The flow characteristics of co-processed material were determined by using an automated, rotary split-level shear tester (iShear, E&G Associates, Franklin, IN) with a preconsolidation stress of 3 kPa. The peak torque required to shear the cell was measured as a function of the applied compressive stress. Quantitative bulk flow information such as the powder internal angle of friction and the unconfined cohesive strength (uniaxial compressive strength) was determined. The internal angle of friction is related to the hardness of the powder particle, surface energy, particle size distribution and the degree of compaction. The uniaxial compressive strength is the powder strength under compression. Higher values indicate higher cohesion and poor flowability.39 The relative flowability index was calculated as the ratio of the consolidation stress to the unconfined cohesive strength. In addition, the flowability of coprocessed material was also determined by using Erweka GT tester (Heusenstamm, Germany). A 200 mL hopper was chosen for the study with an outlet nozzle of 10 mm fixed in the instrument.


12

Page 13 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


A random volume of test sample was filled into the hopper and the test was started. The powder was able to flow freely without need for stirring. The friability of the tablets was tested by accurately weighing 6.5g of tablet samples and placing in the testing drum. The tablets were carefully de-dusted prior to testing. The drum was rotated 100-500 times, and the tablets were removed. Any loose dust from the tablets was removed as before, and the sample was accurately weighted to calculate % weight loss. Dissolution & Bioavailability: Dissolution of 1000 mg strength Met XR tablets (n=3) from a 40 kg API scale co-processed batch, and 1000 mg commercial Met XR tablets (n = 6) was conducted in 1000 mL 50 mM pH 6.8 phosphate buffer at 37°C using the USP apparatus I at 100 rpm. At the specified time interval (60, 180, and 600 minutes from the test initiation), approximately 10 mL aliquot was removed from each dissolution vessel and filtered using 0.45µ PVDF filter. The amount of metformin dissolved was determined by UV-VIS spectrometer (HP 8453) and computed using the UV-Visible ChemStation software. A relative bioavailability study was conducted comparing a single dose of one tablet of 1000 mg Met XR, manufactured by using co-processed material, to single dose of two tablets of 500 mg Glucophage XR (reference product) in healthy 32 subjects, as a randomized, two periods, two treatments crossover study. RESULTS AND DISCUSSION The solubility of metformin HCl is less than 10 mg/mL in both acetone and ethyl acetate solvents. Therefore, metformin HCl crystallized when added into the acetone/ethyl acetate mixture. Agglomerates were visually noticeable within the first 10 minutes following the addition. Figure 3 shows the microscope image of typical agglomerate generated during the process. The image was taken as the agglomerates were still in the mother liquor, before


13


Page 14 of 33

isolation. The surface of the agglomerate is covered with metformin HCl crystals. The HPMC K100M and NaCMC incorporated in the agglomerate appear as transparent (Figure 3, circled in red) due to their swelling behavior.

Figure 3. Microscopic image of an agglomerate generated at the end of the co-processing prior to isolation. The solvent ethyl acetate serves a critical purpose in the co-processing mechanism by sequestering part of the water from the mother liquor into the polymers, HPMC K100M and NaCMC, due to its limited water miscibility. The swelling behavior of HMPC K100M and NaCMC via this mechanism was extensively investigated by using solution calorimetry.40 As the water is absorbed, a gel layer forms at the surface of the HPMC and NaCMC particles,41 allowing the metformin HCl crystals to adhere onto their surface. In addition, the absorbed water contains dissolved metformin HCl, which ultimately crystallizes inside the polymers, providing intimate mixing of metformin HCl and the polymers. The FIB-SEM images support this mechanism; elemental analysis of a cross-section of individual agglomerates indicates presence of Cl, associated with metformin hydrochloride salt but not present in the polymers, inside the agglomerates (Figure 4).


14

Page 15 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. FIB-SEM images of (a,b) cross-section of a tray dried agglomerate at two different magnifications (c) element mapping image for Cl using EDS on SEM The dried co-processed agglomerates typically displayed 0.5-0.7 wt% in loss on drying. The typical residual acetone and ethyl acetate levels were 0.07 wt% and 0.05 wt%, respectively. According to Guideline for residual solvents Q3C (International Conference on Harmonization of Technical Requirements For Registration of Pharmaceuticals For Human Use), acetone and ethyl acetate are class 3 solvents (solvents with low toxic potential), thus the limit of 5000 ppm is acceptable without justification. The results obtained for acetone and ethyl acetate are below the tolerated limits. Hence agglomeration in solvent environment did not result in significant solvent entrapment. For the targeted co-processed material composition of 80 wt% metformin HCl, 16 wt% HPMC K100M and 4 wt% NaCMC, the potency of the agglomerates were measured as 77-78 wt%. The solubility of HPMC K100M and NaCMC in initial and final solvent compositions was negligible. Therefore there was minimal polymer loss to the mother liquor. On other hand, crystallization yield for metformin HCl was 90 wt% based on the concentration of API measured in the mother liquor at the end of the process. Accordingly, the polymer inputs to the process were determined based on the amount of API that crystallize by the end of the process in order to achieve the target composition. The slightly lower potency value compared to the target value for


15


Page 16 of 33

the final product is due to metformin HCl partially being dissolved in wash solvents during the isolation step. Metformin HCl has been reported to display multiple polymorphic forms.42 Polymorphs of a pharmaceutical solid can have different physicochemical properties, which can directly impact the quality and performance of drug products, such as stability, dissolution, and bioavailability.43 Therefore, our goal was to preserve the original polymorphic form of metformin HCl as it recrystallizes in the presence of excipients. By powder X-ray diffraction, we confirmed that the polymorphic form of the co-processed material was similar to that of the commercially supplied metformin HCl, which is known as Form A (Figure 5).

Figure 5. Polymorphic form of co-processed metformin HCl is confirmed as being similar to that of the commercial metformin HCl by powder X-ray diffraction.

Figure 6 shows the SEM images collected on the co-processed agglomerates with


16

Page 17 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


different magnifications. The surface of the agglomerates is mostly covered by the metformin HCl crystals, which are the rod-shape particles. In the image with 5000x magnification, there are noticeable smoother areas on the surface of the agglomerates where the rod-like crystals are partially buried. These areas are likely the polymer portion of the agglomerates, indicating that the polymers and metformin HCl crystals are agglomerated together rather than physically blended. Typical particle size distribution by sieve analysis reveal that average of 9.5 wt% of the particles are larger than 841 µm, 42.6 wt% of the particles are in the size range of 420-841 µm, 18.6% of the particles are in the size range of 250-420 µm, 3.2% of the particles are in size range of 177-250 µm, and 26.1% of the particles are smaller than 177 µm.

Figure 6. SEM images collected on the agitated dried co-processed material with different magnifications.

The intimate mixing of the HPMC and metformin HCl particles is also reflected in the Raman imaging. The Raman spectra for HPMC K100M and metformin HCl are shown in Figure 7. The characteristic peaks for HPMC K100M and metformin HCl are selected as 738 cm-1 and 1369 cm-1, respectively. No peak position shift is observed in spectra of the co-processed material, indicating there is no chemical interaction between metformin and HPMC after co-


17


Page 18 of 33

processing. The comparison between Raman spectra of as-is and co-processed API can be found in Appendix 1. The co-processed material displays the same spatial distribution for metformin and HPMC, indicating that metformin and polymer occupy the same location, suggesting that they are physically embedded in each other. In contrast, the Raman images from physical blends of metformin HCl and HPMC K100M show that in areas where metformin distribution is high (red or green color), HPMC distribution is low (blue color). Similarly, where HPMC distribution is high, metformin distribution is low. This indicates that there is no spatial correlation between metformin HCl and polymer in the physically blended powders, as expected.

Figure 7. Raman spectra of (a) metformin and (b) HPMC K100M, with unique peaks indicated, Raman imaging of physical blends of metformin HCl and HPMC K100M (c, d) using 738 cm-1 (c) and 1369 cm-1 (d) signal, compared to co-processed metformin HCl agglomerates (e, f) using


18

Page 19 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


738 cm-1 (e) and 1369 cm-1 (f) signal illustrate the intimate mixing that occurs with coprocessing The intimate mixing of metformin HCl, HPMC and NaCMC via co-processing can minimize segregation in downstream processing, which is a risk factor in the benchmark formulation. The strength of the co-processed agglomerates was evaluated by GIT. The results are given in Table 1. The GIT index was found to be

Novel Co-processing Methodology to Enable Direct Compression of a

Recommend Documents