Spherical Cocrystallization - an enabling technology for the

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Spherical Cocrystallization - an enabling technology for the development of high dose direct compression tablets of poorly soluble drugs Hongbo Chen, Yiwang Guo, Chenguang Wang, Jiangnan Dun, and Changquan Calvin Sun Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00219 • Publication Date (Web): 28 Feb 2019 Downloaded from http://pubs.acs.org on February 28, 2019

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Crystal Growth & Design

Spherical Cocrystallization - an enabling technology for the development of high dose direct compression tablets of poorly soluble drugs Hongbo Chen, Yiwang Guo, Chenguang Wang, Jiangnan Dun, and Changquan Calvin Sun*

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

*Corresponding author Changquan Calvin Sun, Ph.D. 9-127B Weaver-Densford Hall 308 Harvard Street S.E. Minneapolis, MN 55455 Email: [email protected] Tel: 612-624-3722 Fax: 612-626-2125

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Crystal Growth & Design 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

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Abstract Spherical cocrystallization (SCC), an integrated crystal and particle engineering approach, was successfully applied to generate spherical cocrystal agglomerates (SCA) between a poorly soluble drug, griseofulvin (GSF) and acesulfame (Acs). The SCC process consists of two steps: 1) GSF-Acs cocrystal formation by reaction crystallization in a slurry, 2) agglomeration by adding a bridging liquid. The obtained SCA exhibited superior mechanical and powder properties over GSF. Inclusion of a small amount ( 100

6

mg), manufacturability is a key challenge.2, 3 The CU challenge for low dose drugs can be very

7

effectively addressed using a versatile platform DC tablet formulation employing particle

8

engineering that involves forming a drug – carrier composite.4 However, an effective strategy for

9

solving the manufacturability challenge facing the development of high dose APIs by the DC

10

process is lacking.

Additionally, APIs exhibiting solubility limiting bioavailability is

11

approximately 80-90% of the new chemical entities in pharmaceutical pipeline.5 For such APIs,

12

solubility in gastric and intestinal fluids must be sufficiently high to achieve adequate

13

bioavailability if permeability does not limit API absorption. For a given solid form of an API, a

14

common practice to alleviate solubility limiting bioavailability is API size reduction, which can

15

enhance dissolution rate by the virtue of larger API surface area.6,

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particles correspond to poorer flowability,8 which deteriorates flowability of the blend if the

17

same API loading is used in the tablet formulation. Hence, manufacturability problems may be

18

encountered depending on the dose and flowability of the size-reduced API powder. One way to

19

address such flow related manufacturability problems is to use lower API loading by using a

20

larger tablet. However, larger tablets are generally undesirable because of the lower patient

21

compliance.9

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However, smaller API

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An alternative approach to improve API bioavailability is the use of soluble solid form,

23

such as amorphous solid, cocrystal, and salts.10 Among these solid forms, cocrystal is attractive 3 ACS Paragon Plus Environment


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because it exhibits better physical stability than amorphous solids during storage and it is

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applicable to non-ionizable APIs that are not amenable to salt formation.11

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presence of coformer in cocrystal necessarily increases the loading in the formulation for the

27

same API amount. This presents an additional challenge for high dose APIs if the more soluble

28

cocrystal does not exhibit desired flow or tableting properties, which likely dominate

29

manufacturability of the blend.2, 12

However, the

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Spherical crystallization is a process that directly transforms fine crystals into compact

31

spherical agglomerates during the crystallization process.13-16 For a given crystal form, spherical

32

crystallization has been found effective in improving powder flowability, packability,

33

compressibility, and tabletability on study such as lactose,17 albendazole,14 tolbutamide,18

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acebutolol hydrochloride19 and etodolac20. In favorable cases, DC tablet formulation containing

35

as high as 99% API could be attained by using spherical agglomerates.21

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It would be reasonable to expect that spherical cocrystallization (SCC), which combines

37

spherical crystallization and cocrystallization, can simultaneously improve manufacturability and

38

dissolution performance of drugs to enable the development of DC tablet formulations of high

39

dose APIs. In this sense, SCC is a true integrated API crystal and particle engineering strategy

40

that can be potentially very useful to pharmaceutical tablet development and manufacturing.

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SCC was firstly reported on the energetic material ammonium nitrate to produce smokeless and

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easy

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carbamazepine/saccharin cocrystal agglomerates.23 Moreover, it can be used to control the

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cocrystal stoichiometry and particle size.24 Surprisingly, SCC has not been explored to improve

45

the manufacturing and dissolution performance of poorly soluble APIs in high dose tablets. The

46

goal of this work was to fill this knowledge gap using a high dose model drug, griseofulvin

packing

cocrystal

agglomerates.22

Similarly,

it

was

applied

to

generate


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(GSF), which is challenging to formulate by DC process because of its poor powder flowability

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and tabletability in addition to low solubility (10 μg·ml-1 at 37 oC).25

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Materials and methods

50

Materials

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Griseofulvin (GSF; Glaxo Laboratories, London, UK), Acesulfame potassium (Acs-K, Tokyo

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Chemical Industry Co., Ltd., Japan), fumed silica (CAB-O-Sil, M5-P, Cabot Corporation, Boston,

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MA), microcrystalline cellulose (Avicel PH105; FMC Biopolymers, Newark, DE),

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croscarmellose sodium (CCM-Na, SD-711, FMC Biopolymer, Philadelphia, PA), magnesium

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stearate (MgSt, Mallinckrodt Inc., St. Louis, MO), Hydroxypropylcellulose (HPC, EF Pharm,

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Ashland., Wilmington, DE), and Dichloromethane (DCM, Fisher Scientific, Fair Lawn, NJ) were

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received from respective manufacturers and were used as received.

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Preparation of spherical GSF-Acs cocrystal hydrate

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A mixture of 0.01 mol of GSF and 0.01 mol of Acs-K was suspended in 70 mL of methanol and

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water (2:8, v/v) mixture. Concentrated hydrochloric acid (1 mL) was added to convert the Acs-

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K into acesulfame free acid (Acs-H) completely. The suspension was agitated overnight. This

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reaction crystallization led to phase pure fine GSF-Acs crystals, which was a monohydrate.25

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The suspension was cooled to 0 oC in an ice-bath and stirred at 500 rpm using an overhead mixer.

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Under stirring, DCM was added dropwise into the suspension until the initially turbid medium

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became clear, which corresponded to the elimination of fine crystals from the suspension. Then,

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the agitation was continued for 1h before filtration and drying at 60 oC for 4 hr. In some batches,

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HPC (35 mg) was added to the vessel before DCM was added to improve wettability of



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agglomerates.26 Subsequent steps were the same as the process without HPC. DCM was a

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bridging liquid that facilitated the agglomeration of fine GSF crystals.

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Powder X-ray Diffractometry (PXRD)

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A powder X-ray diffractometer with Cu Kα radiation (1.54059 Å) was used to characterize

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crystallographic properties of samples. Samples were scanned between 5 to 35° 2θ with a step

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size of 0.02° and a dwell time of 1 s/step. The X-ray tube voltage and amperage were 40 kV and

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40 mA, respectively. A theoretical PXRD pattern of GSF-Acs was calculated from the single

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crystal structure (CCDC refcode: GEPJIW).25 Thermal Analyses

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Powder samples (3−5 mg) were loaded into hermetically sealed aluminum pans (Tzero) and

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heated from 30 to 200 °C at a rate of 10 °C/min using a differential scanning calorimeter (Q2000,

78

TA Instruments, New Castle, DE). The sample was purged with nitrogen at a flow rate of 50

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mL/min. The instrument was equipped with a refrigerated cooling system. The temperature and

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cell constant were calibrated using high purity indium.

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Scanning electron microscopy (SEM)

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A thin layer platinum (thickness ~ 75 Å) was sputter-coated onto the samples, which were

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mounted onto carbon tapes, using an ion-beam sputter (IBS/TM200S; VCR Group Inc., San

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Clemente, CA). The particle morphology and surface features were evaluated by scanning

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electron microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan), operated at SEI mode with an

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acceleration voltage of 5kV. A high vacuum (10-4-10-5 Pa) was maintained during the imaging

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process.


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Contact angle measurement

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Tablets, prepared by compressing powders at 300 MPa, were used for contact angle

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measurements using the sessile drop method on a goniometer (MAC-3, Kyowa Interface Science

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Co. Ltd., Japan). A drop of distilled water (∼2 μL) was gently placed on the surface of the tablet

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using a syringe dispenser. The image of the water drop was recorded from the side every 67 ms

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for 60 s using a high-speed camera. The angle between the sample surface and the tangent line at

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the edge of the drop was determined using image analysis software, FAMAS3.72 (Kyowa

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Interface Science Co. Ltd., Japan). Three measurements were made at different locations on each

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tablet, and the mean and standard deviations were calculated.

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Energy framework and topologic analysis of crystal structures

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The pairwise intermolecular interaction energy was estimated using CrystalExplorer and

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Gaussian09W with experimental geometry of GSF-Acs monohydrate and GSF (Form I, CSD

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refcode: GRISFL06).27-29 The hydrogen positions were normalized to standard neutron

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diffraction values before calculation using the B3LYP-D2/6-31G(d,p) electron densities model.

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The total intermolecular interaction energy for a given molecule is the sum of the electrostatic,

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polarization, dispersion, and exchange-repulsion components with scale factors of 1.057, 0.740,

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0.871, and 0.618, respectively. Intermolecular interaction between two molecules is ignored

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when the closest atom - atom distance was more than 3.8 Å. The interaction energies were

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graphically presented as a framework by connecting centers of mass of molecules with cylinder

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thickness proportional to the total intermolecular interaction energies, where interaction energies

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less than -5 kJ/mol were omitted for clarity. The crystal packing topology was analyzed using a

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python program.30



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Formulation and Tablet Compression

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MCC (Avicel PH105) was used as a tablet binder because of its excellent tabletability.31

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However, the flowability of Avicel PH105 is poor. Thus, it was coated with nano silica particles

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using a dry comilling process to improve its flowability before mixing with API.32 Briefly, 50 g

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of Avicel PH105 and colloidal silica (1.0% loading) were geometrically mixed and passed

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through a sieve (150 µm opening). The powder mixture was then placed in the Comil chamber

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and passed through a stainless-steel screen (round holes of 0.9905 mm, or “0.039”, diameter; part

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number: 7B039R03125) with an impeller speed of 2200 rpm. The process was repeated 40 times

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to ensure uniform distribution of silica particles onto Avicel PH105 particles. API and all other

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excipients (Table 1), totaling 5 g, were added to a 30 mL plastic bottle, which was manually

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rotated diagonally to allow particles slide and mix for 15 min (approximately 900 turns).

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A universal material test machine (model 1485, Zwick/Roell, Germany) was used to prepare

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tablets with compaction pressure ranging from 25 to 350 MPa at a speed of 4 mm/min. The

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punch tip and die wall were coated with a 5% (w/v) magnesium stearate suspension in ethanol

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and then dried with a fan. Tablets were relaxed under ambient environment for at least 24 h

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before being broken diametrically using a texture analyzer (TA-XT2i; Texture Technologies

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Corporation, Scarsdale, NY). Tablet tensile strength was calculated from the breaking force (F)

127

and tablet thickness (h) and diameter (d) using equation (1).33 Tablet flashing was carefully

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removed to improve accuracy of measured tablet thickness.34

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𝜎 = 𝜋𝑑ℎ

130

Powder Flowability

2𝐹

(1)


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Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar Schulze,

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Wolfenbüttel, Germany), with a 10 mL cell at 1 and 3 kPa pre-shear normal stresses. A yield

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locus was obtained by conducting shear test under different normal stresses, from which the

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unconfined yield strength (fc) and major principal stress (σn) were obtained by drawing Mohr’s

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circles. The flowability index (ffc) was calculated using Eq. (2): 𝜎𝑛

(2)

𝑓𝑓c = 𝑓c 136

Expedited Friability

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An expedited friability method was applied to determine the ability of compressed tablets to

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resist wearing and abrasion.35 Coded tablets prepared under different pressures were weighted,

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coded, and loaded into a friabilator (Model F2, Pharma Alliance Group Inc., Santa Clarita, CA)

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at 25 rpm for 4 min. The final weight of each tablet was used to calculate percent weight loss,

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which was plotted against compaction pressure to construct a friability plot. The compaction

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pressure corresponding to 0.8% tablet weight loss was identified from the friability plot.35

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Artificial Stomach-Duodenum Dissolution (ASD)

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Although the griseofulvin is non-ionizable, the coformer of acesulfame (pKa=2.0) shows strong

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acidity nature. Therefore, the solubility of griseofulvin - acesufulame cocrystal is expected to be

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pH-dependent. Dissolution results in the single chamber apparatus, such as USP method, may

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not reflect the real condition and result in wrong conclusion. Thus, using ASD apparatus with

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two chambers (pH 1.2 and 6.8) is a more reliable approach.

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The ASD apparatus consisted of two jacketed beakers that were connected using a short tubing,

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mimicking stomach chamber and duodenum chamber, respectively. The temperature was kept at

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37 °C by circulating water. Fluid flow from stomach chamber to duodenum chamber was 9 ACS Paragon Plus Environment


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regulated by a programmed peristaltic pump (Masterflex L/S Easy-Load II pump, Cole-Parmer,

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Vernon Hills, IL).36

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To simulate human physiological conditions in the fasted state, 0.1 N HCl (pH = 1.2) was

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prepared for gastric liquid in stomach and 0.1 M sodium phosphate buffer (pH = 6.8) for the

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duodenum. The initial volume of the stomach chamber was 250 mL, which was emptied to 50

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mL, following a first-order kinetics with a half-life of 15 min to simulate stomach empty process.

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Throughout the entire experiment, the fluid volume in the duodenum chamber was maintained at

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30 mL, achieved by setting a vacuum line at a calibrated height. In addition, the two chambers

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were infused with fresh gastric or duodenal secretion liquid at 2 mL/min to mimic in vivo

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secretion processes. A fiber optic UV/Vis probe was used to monitor the drug concentration.

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Mixing was achieved by an overhead paddle stirrer in the stomach chamber and a magnetic

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stirrer in the duodenum chamber. Prior to each experiment, calibration of all pumps and

164

spectrometers were performed. All fluids used in the experiment were degassed to avoid the

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generation of bubbles that may interfere the data collection using the UV dip probe.

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The drug concentration−time profile in the duodenum was analyzed, using the non-

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compartmental method (PKsolver 2.0) to determine the peak plasma concentration (Cmax), time

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to reach Cmax (Tmax), and area under the plasma concentration−time curve (AUC).37

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170

Results and discussion

171

Characterization


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The as-received GSF crystals were 1-5 µm in size and with irregular shape (Figure 1a).

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The GSF-Acs cocrystals (GSF-Acs) from reaction crystallization were prism shape with size

174

ranging 1 - 10 µm. The primary crystals in the cocrystal agglomerates without HPC (GSF-

175

Acs/SA) and with HPC (GSF-Acs/HPC) were comparable to those in the GSF-Acs, indicating

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that the addition of DCM and HPC did not significantly influence the property of the primary

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GSF crystals (Figure 1). This is understandable since the cocrystal forming process was identical

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in all cases. The subsequent introduction of bridging liquid and HPC affects, at most, attrition

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and ripening of these primary crystals. a)

b)

c)

d)

180 181

Figure 1. SEM images of a) GSF, b) GSF-Acs, c) GSF-Acs/SA and d) GSF-Acs/HPC.

182 183

The size of the GSF-Acs/HPC was much smaller compared to that of the GSF-Acs/SA

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(Figure 2 & Figure S1). The smaller size of GSF-Acs/HPC is attributed to the impact on the

185

agglomeration process by changes in surface tension between bridging liquid and bulk medium 11 ACS Paragon Plus Environment


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or medium viscosity by the introduction of HPC.

Although smaller, the GSF-Acs/HPC

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agglomerates were more spherical than GSF-Acs/SA (Figure 2a & 2b). Similar effect of HPC on

188

size and shape of spherical agglomeration was reported for etodolac.38

189 (a)

190

(b)

Figure 2. Microscopy images of (a) GSF-Acs/HPC and (b) GSF-Acs/SA.

191 192

PXRD patterns of the GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC all matched well with

193

the calculated pattern from the GSF-Acs crystal structure (Figure 3). The slight shift of some

194

peaks to higher 2θ values in the calculated PXRD pattern is attributed to the thermal expansion

195

of crystal lattice since the crystal structure used for calculating PXRD pattern was solved at 100

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K while the experimental PXRD patterns were obtained at ~298 K. The largest 2θ shift (~0.5o)

197

observed in 27.2o and 28.3o is attribute the ease of crystal thermal expansion along the (0 6 0)

198

and (0 6 1) planes. This is consistent with the fact that absence of strong interlayer hydrogen

199

bonds interaction between the (0 2 0). Moreover, characteristic peaks of the starting materials

200

were absent in the experimental PXRD patterns, confirming their phase purity. DSC

201

thermograms of the three different GSF-Acs powders (Figure S2) were all similar to the reported


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data with two endotherms between 130-160 oC and 170-190 oC, respectively.25 Collectively, the

203

phase purity of all three GSF-Acs powders was confirmed.

204 205

Figure 3. PXRD patterns of Acs-H, GSF, GSF-Acs/HPC, GSF-Acs/SA, GSF-Acs, and

206

calculated GSF-Acs.

207

The tabletability, i.e., tensile strength vs. compaction pressure, of the as-received GSF

208

was very poor as no intact tablets could be prepared due to lamination (Figure 4). The fine GSF-

209

Acs showed slightly improved tabletability with a maximum tensile strength of ~ 0.4 MPa at 100

210

MPa compaction pressure (Figure 4). Intact tablets were so weak that very gentle handling was

211

required when measuring their breaking strength. Extensive tablet lamination still occurred when

212

the compaction pressure was higher than 150 MPa. The tableting performance of the GSF-

213

Acs/SA was similar to GSF-Acs, except lamination was observed earlier at 100 MPa compaction

214

pressure. The GSF-Acs/HPC exhibited much better tabletability compared to GSF-Acs and GSF-

215

Acs/SA. In fact, the highest tensile strength of GSF-Acs/HPC was 2.5 MPa at a compaction

216

pressure of 150 MPa. The similar tableting performance of GSF-Acs and GSF-Acs/SA indicated

217

that extensive fracture of the agglomerates had occurred, which eliminated the potential effect on 13 ACS Paragon Plus Environment


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tabletability by the larger agglomerate size and microstructure of the SA. HPC is a good tablet

219

binder.39,

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indicated uniform coating of GSF-Acs crystals by HPC.38 Such polymer distribution is effective

221

in attaining an extensive three dimensional bonding network in the tablet with increased inter-

222

particular bonding area.41, 42

40

The improved tabletability of GSF-Acs/HPC at such a low level of HPC (< 1%)

223 224

Figure 4. Tabletability profiles of pure GSF, GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC.

225 226

It has been demonstrated the solid forms with excellent compaction properties usually

227

display active slip/cleavage planes with lower interlayer interaction energy and smooth plane

228

topology, which facilitate plastic deformation.27 However, clear identification of the active slip

229

planes in both GSF and GSF-Acs is challenging by visualization of crystal structures.43 While

230

GSF showed no strong hydrogen bonds in its structure and the GSF-Acs exhibited three-

231

dimensional hydrogen bonds network, neither shows visually clear molecular layers that can

232

serve as active slip planes. The energy framework of both crystal structures suggested an absence

233

of crystallographic planes that can serve as active slip planes with much weaker interlayer

234

interactions (Figure 5, also see Table S1 for detailed intermolecular interaction energies). 14 ACS Paragon Plus Environment

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235

Additionally, all the interlayer distances computed by topology analysis are negative, implying

236

interlocking between possible molecular layers, which hindered the slip among them. For

237

example, the most likely slip planes based on topology analysis, (0 1 1) for GSF and (1 -1 1) for

238

GSF-Acs, had interplanar overlapping of-3.80 Å and -1.72 Å, respectively. Thus, neither GSF

239

(Form I) nor GSF-Acs exhibits crystal structure that promotes plasticity, which is essential for

240

forming strong tablets. This is consistent with the very poor tabletability of both crystals (Figure

241

4). a)

b)

242 243 244

Figure 5. Energy frameworks of a) GSF, and b) GSF-Acs, both viewed into a axis of corresponding unit cell. The interaction energy threshold was set at −5 kJ/mol.

245 246 247

Formulation development A successful formulation for tablet product development needs to meet several criteria: (1)

248

adequate blend flowability for smooth and reproducible hopper emptying and die filling, which

249

are critical for sustaining high speed tableting, (2) adequate mechanical strength of the tablet

250

(tabletability), (3) low friability, and (4) adequate dissolution performance. For APIs exhibiting

251

poor tabletability that still need to be delivered in high doses, such as GSF, the use of tablet

252

binders with excellent tabletability is necessary to assure adequate tabletability of the final 15 ACS Paragon Plus Environment


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formulation. Avicel PH105 was chosen in this work because of its excellent tabletability.31 The

254

70% loading of GSF-Acs (corresponding to 55.7% GSF) was used (Table 1), since lamination

255

was observed when cocrystal loading was 80%.

256

Table 1. Formulation Composition of GSF-containing tablet using different powder forms Components (%)

Function

GSF

GSF-Acs

GSF or GSF-Acs

Active

55.7

70

70

70

Silica coated MCC PH105

Dry binder

38.8

24.5

24.5

24.5

CCS-Na

Disintegrate

5

5

5

5

Magnesium stearate

Lubricant

0.5

0.5

0.5

0.5

100

100

100

100

Total

GSF-Acs/SA GSF-Acs/HPC

257

All formulations exhibited good tabletability, where tablet tensile strength could reach 2

258 44

259

MPa

at a compaction pressure above 120 MPa. The tabletability of formulations containing

260

GSF-Acs, GSF-Acs/SA, or GSF-Acs/HPC was similar, which was lower than the formulation

261

containing GSF (Figure 6a). Based on the friability plots (Figure 6b), all formulations met the

262

minimum friability requirement of < 0.8% when the compaction pressure was higher than 250

263

MPa.35 The GSF formulation exhibited the best friability, which required no more than 150 MPa

264

in order to attain < 0.8% friability (Figure 6b). The superior tabletability and friability of the GSF

265

formulation is reasonable because it contained about 60% higher amount of highly compressible

266

Avicel PH105 than other three formulations (Table 1). Therefore, it is expected that both

267

tabletability and friability of this formulation is better.45 It is interesting to note that the

268

tabletability of the formulation containing GSF-Acs/HPC was the same as other two GSF-Acs 16 ACS Paragon Plus Environment

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containing formulations, despite the significantly better tabletability of GSF-Acs/HPC (Figure 4).

270

This highlights the difficulty in accurately predicting tabletability of a mixture from constitutive

271

components and the need for mechanistic investigation into compaction behavior of mixtures.46,

272

47

273 a)

b)

274 275 276

Figure 6. Manufacturability of formulated GSF, GSF-Acs, GSF-Acs/SA, and GSF-Acs/HPC, (a) tabletability and (b) friability.

277 278

Another important property of a successful tablet formulation is the flowability. Only

279

GSF-Acs/HPC and GSF-Acs/SA formulations exhibited flowability better than that desired for

280

high speed tableting, marked by Avicel PH102 (Figure 7).48 The differences in flowability are

281

attributed to the different particle sizes and shapes of the API powders used in these formulations.

282

Both GSF-Acs and GSF consisted of small elongated crystals (Figure 1), while both GSF-

283

Acs/SA and GSF-Acs/HPC consisted of large and more round agglomerates (Figure 2).8

284



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285 286

Figure 7. Flowability plots of formulated GSF, GSF-Acs, GSF-Acs/SA and GSF-Acs/HPC.

287 288

Having verified the acceptable manufacturability of both formulations containing GSF-

289

Acs agglomerates, we then assessed the dissolution performance of formulated tablets using the

290

ASD apparatus. All three cocrystal formulations released GSF more rapidly than the formulation

291

of GSF. Both the AUC and Cmax followed the order of GSF-Acs/HPC > GSF-Acs >> GSF-

292

Acs/SA > GSF (Figure 8a, Table 2). The enhanced dissolution performance of the cocrystal

293

formulations compared to that of GSF may be attributed to the approximately 3 fold higher

294

solubility of GSF-Acs than GSF.25 The time to reach Cmax, i.e., Tmax, is longer for formulation

295

that exhibited higher Cmax, which is reasonable.


Page 19 of 25 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)

296 297 298 299

b)

Figure 8. (a) ASD duodenum concentration profiles for formulated GSF, GSF-Acs, GSF-Acs/SA and GSF-Acs/HPC tablets prepared at 250 MPa, (b) wettability of GSF-Acs/HPC, GSF-Acs/SA and GSF-Acs.

300 301

Table 2. Simulated pharmacokinetic parameters of various GSF-containing tablets (n =3)

302

GSF

GSF-Acs

GSF-Acs/SA

GSF-Acs/HPC

303

Tmax (min)

20 ± 0.0

20 ± 0.0

25 ± 7.1

23 ± 4.2

304

Cmax (μg/ml)

15.3 ± 0.2

47.9 ± 1.6

21.1 ± 0.8

51.5 ± 3.4

305

AUC0-t (μg/ml min)

1394 ± 55

3255 ± 152

1910 ±264

3697 ± 297

306 307

To further understand the different dissolution performance of the three cocrystal

308

formulations, wettability of the pure APIs was assessed using contact angle measurement.

309

Contact angle of GSF could not be determined using this method because it did not form intact

310

tablets. However, it is expected to be high given its significantly lower aqueous solubility.

311

Contact angle of pure cocrystal samples follow the order of GSF-Acs/SA> GSF-Acs > GSF-

312

Acs/HPC (Figure 8b). Thus, GSF-Acs/HPC exhibited better wettability than GSF-Acs/SA and 19 ACS Paragon Plus Environment


Page 20 of 25

313

GSF-Acs. The better wettability of GSF-Acs/HPC is consistent with the better dissolution of the

314

GSF-Acs/HPC tablet, despite its much larger size of GSF-Acs/HPC than GSF-Acs. This suggests

315

that wetting is a key step in the dissolution of GSF-Acs from tablet. The effect of surface area of

316

API on dissolution is shown by the significantly faster dissolution from tablet containing GSF-

317

Acs than that containing GSF-Acs/SA (Figure 8a), although wettability of pure API powders was

318

only slightly different (Figure 8b). Thus, the overall effect of both faster wetting and larger API

319

size of GSF-Acs/HPC led to dissolution performance of its tablet comparable to that of GSF-Acs

320

tablet (larger surface area and intermediate wetting), both were significantly better than GSF

321

(poor wetting and large area) and GSF-Acs/SA (small surface area and intermediate wetting)

322

formulations.

323 324

The overall performance of each formulation considering manufacturability and

325

dissolution is summarized in Table 3. Only the GSF-Acs/HPC formulation exhibited acceptable

326

manufacturability and significantly improved dissolution performance. Both the GSF and GSF-

327

Acs formulation suffered poor flowability due to the small size and poor flowability of API.

328

Thus, they are unfit for commercial tablet manufacturing. The GSF-Acs/SA formulation

329

exhibited good manufacturability but only marginal improvement in dissolution. Therefore, only

330

the use of GSF-Acs/HPC successfully enabled a high dose DC tablet formulation of GSF, which

331

was both manufacturable and fast releasing.

332 333 334


Page 21 of 25 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


335 336 337 338 339 340 341 342

Table 3. Summary of various GSF tablet formulations in meeting key criteria (meeting– Y, not meeting – N) Formulation

Tabletability Friability (≥ 2 MPa) (≤ 0.8%)

GSF GSF-Acs GSF-Acs/SA GSF-Acs/HPC

Y Y Y Y

Y Y Y Y

Flowability (better than Avicel PH102) N N Y Y

Dissolution

Overall

N Y N Y

N N N Y

343 344

Conclusions

345

In this work, an integrated crystal and particle engineering approach, spherical

346

cocrystallization (SCC), was used to prepare GSF-Acs spherical agglomerates exhibiting both

347

improved manufacturability and dissolution performance. Such spherical cocrystals enabled the

348

development of a high GSF loading (55.7%) direct compression tablet formulation suitable for

349

manufacturing of GSF tablets with enhanced dissolution performance. The simultaneous

350

improvement of tablet manufacturability and dissolution by SCC is a powerful approach that

351

may have broad applicability to enable the successful development of high dose tablets of other

352

poorly soluble drugs.

353 354

References

355 356 357 358 359 360 361 362

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473


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474 475

TOC

Spherical cocrystallization

476

Manufacturability

Dissolution

477 478 479

Synopsis. Spherical agglomeration of a more soluble acesulfame cocrystal exhibit better tablet manufacturability and dissolution of griseofulvin.

480 481


Spherical Cocrystallization - an enabling technology for the

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