Kinetics Study of Cocrystal Formation Between Indomethacin and Saccharin Using High-Shear Granulation With In Situ Raman Spectroscopy

Journal of Pharmaceutical Sciences 108 (2019) 3201-3208

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Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Kinetics Study of Cocrystal Formation Between Indomethacin and Saccharin Using High-Shear Granulation With In Situ Raman Spectroscopy Ryoma Tanaka 1, 2, Yusuke Hattori 1, 3, Kazuhide Ashizawa 3, Makoto Otsuka 1, 3, * 1 2 3

Graduate School of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455 Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 February 2019 Revised 6 June 2019 Accepted 20 June 2019 Available online 4 July 2019

Pharmaceutical manufacturing processes are necessary to make solid dosage form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (g-form, a-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using AvramieErofeev or GinstlingeBrounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry. © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Keywords: cocrystal crystallization crystal structure crystal engineering kinetics granulation Raman spectroscopy chemometrics process analytical technology continuous processing

Introduction Drug dissolution profile and solubility of the pharmaceutical solidstate form are major factors that influence gastrointestinal permeability, bioavailability, and clinical response according to the Biopharmaceutical Classification System (BCS).1 Enhancements in the dissolution profile and solubility of BCS class II/IV drugs are considered one of the most challenging aspects of drug development because poorly water-soluble drugs cause various problem in relation to the bioavailability or manufacturing process.2 In recent developments of drug candidate compounds, many new drug candidates show low solubility, and this number is increasing.3 The mentioned problem may influence in vitro study in the discovery stage and becomes a reason for delays in the creation of new drugs.4 In particular, BCS class II drugs have low solubility and high permeability, thus the dissolution process is the rate-determination step in drug absorption.1

* Correspondence to: Makoto Otsuka (Telephone: þ81 42 468 8658). E-mail address: [email protected] (M. Otsuka).

Preparation of pharmaceutical molecular complexes with active pharmaceutical ingredients (APIs) have been investigated to improve properties such as the stability and solubility of drug molecules.5,6 Reported crystalline complexes of the API with excipient include hydrates/solvates,7,8 salts,9 cocrystals,6,10 and their polymorphs.11,12 On the other hand, amorphous complexes have been reported by several publications regarding amorphous solid dispersions and coamorphous systems.13,14 Among them, current attention toward cocrystal engineering because crystalline solids are more thermodynamically stable than amorphous, and they can flexibly improve properties of APIs.6,10 According to Food and Drug Administration,15 the multicomponent solids are composed of an API with one or more pharmaceutical excipients such as a coformer which is not a solvent and typically nonvolatile. The cocrystals have noncovalent interactions in the crystal lattice such as hydrogen bonding, whereas salt formations have an acidbase reaction between the API and an acidic or basic substance.16 From a regulatory information, cocrystal is classified similar to polymorph of API and not regarded as a new API. When the cocrystal product is administered in human body, the API should be

https://doi.org/10.1016/j.xphs.2019.06.019 0022-3549/© 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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subsequently dissociated from cocrystal before reaching the target site of pharmacological activity. The engineering of cocrystals has offered an innovative approach to enhance physicochemical,17 mechanical,18,19 and biopharmaceutical properties.20 When the cocrystal products of APIs are created in the pharmaceutical industry, additional pretreatment is required for cocrystallization, for example, slow solvent evaporation,17 slurry method,21 and mechanical grinding.22,23 However, a reduction in the number of operations is ideal for producing a final pharmaceutical product in industry. Additionally, the general manufacturing process consisted of such as mixing, granulation, drying, and tableting which is necessary to make a solid dosage formulation influence the final crystalline form.11 Hence, another method to straighten out these problem is forming the cocrystals over the duration of a 1-step manufacturing processes. A scalable wet granulation can improve the granule properties such as flowability and uniformity, and the continuous 1-step process is employed in the pharmaceutical industry.24,25 A combination of wet granulation and in situ analysis for continuous manufacturing has been developed recently.25,26 Process control based on process analytical technology and quality-by-design are pivotal concepts for the pharmaceutical industry to produce consistent quantities of high-quality products.27 Nondestructive and in situ spectroscopy methods have been used to monitor and control the pharmaceutical processes, such as Raman spectroscopy,28 near-infrared spectroscopy,29 and so on.30-32 Raman spectroscopy is known as an effective way to study bond vibrational energies in the crystal structure.33 Many authors used Raman to selectively distinguish between the crystal structures of an API.34,35 The obtained multivariable spectra data during pharmaceutical processes are required for quantitative analysis using chemometrics, for instance, multivariate curve resolution (MCR),36,37 partial least squares regression,38 or 2-dimensional correlation spectroscopy.39 The reasons why chemometrics has been used are for noise reduction, prevention of multicollinearity, characterization, and statistical control.40 Indomethacin (IND) is known as a typical weakly acidic model drug (pKa 4.5) of BCS class II and was reported to form a cocrystal with saccharin (SAC), which can enhance solubility and bioavailability of IND.41-43 In this study for the purpose of making the INDSAC cocrystal product during the consistent process, and the granules were prepared using a high-shear wet granulation method without the preprocess of cocrystal formation. The methodology allows the continuous manufacture of pharmaceutical products as a cocrystal; therefore, it is required to monitor any crystalline structure changes in the API and control the processes by in situ analysis. IND and SAC reaction kinetics dependent on the binding solvent systems or initial thermodynamic state of IND were investigated using Raman spectroscopy and chemometrics of MCR by alternative least-squares (MCR-ALS) analysis during high-shear granulation. The crystalline states and dissolution properties of obtained granules and tablets were also analyzed, respectively.

Figure 1. The crystalline structures of (a) IND with atom numbering and (b) IND-SAC cocrystals. The light blue broken lines and green values indicate the hydrogen bonding and distance in Å between 2 atoms, respectively.

chemical structure is presented in Figure 1a. All other chemicals were commercially available chemicals of analytical grade. The solid polymorph IND alpha-form (a-form) was prepared by following a recrystallization method: 10 g of IND g-form was dissolved in 10 mL of ethanol and heated to 80 C, then 20 mL of water was added, and a precipitate was obtained with the use of a vacuum dryer (AVO-200NB; AS ONE, Osaka, Japan) at 40 C for 12 h. To prepare an amorphous solid of IND (AMS), 5 g IND g-form was milled using a planetary ball mill (P-6; Fritsch, Idar-Oberstein, Germany) with 10 agate balls (4 20 mm) at 4 C for 6 h. The reference IND-SAC cocrystal was prepared using a modified slurry method with a resonant acoustic mixer.44 The equipment used was a Resonant Acoustic LabRAM (Resodyn, Butte, MT). The equimolar mixture between IND (1.32 g; 0.36 mmol) and SAC (0.68 g; 1.00 eq) with 10 mL ethanol was weighed into a 50 mL vial. The vial was sealed and placed in a sample holder, then the sample was mixed at a constant frequency of 60 Hz and

Materials and Methods Materials As additives, a-lactose monohydrate (Pharmatose 200M), microcrystalline cellulose (Ceolus PH-102), hydroxypropyl cellulose, and SAC (cofomer) were purchased from DFE Pharma (Goch, Germany), Asahi Kasei Chemicals (Tokyo, Japan), Nisso (Tokyo, Japan), and Fujifilm Wako Pure Chemical (Osaka, Japan), respectively. Commercial crystalline IND gamma-form (g-form) as the API was purchased from Tokyo Chemical Industry (Tokyo, Japan). The IND

Table 1 Materials Used for Preparing Granules and Tablets Exp.

INDa, g

SACb, g

LAMc, g

MCCd, g

HPCe, g

Total, g

Refs 1-2 Runs 1-4

1.32 1.32

0.00 0.68

1.74 1.26

0.74 0.54

0.20 0.20

4.00 4.00

a b c d e

Indomethacin. Saccharine. Lactose monohydrate. Microcrystalline cellulose. Hydroxypropyl cellulose.

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Table 2 Formulation and Granulation Process Parameters No.

Crystal Form of Indomethacin

Solvent System

Additive Rate of Solvent, mL/min

Ref 1 Ref 2 Run 1 Run 2 Run 3 Run 4

g-form g-form g-form g-form a-form

Water Ethanol Water Ethanol Ethanol Ethanol

60 80 60 80 80 80

amorphous

acceleration of 980 m/s2 for 300 s. The slurry was dried using a vacuum dryer at 40 C for 12 h. The crystalline structure of INDSAC cocrystals has been reported previously using a single crystal X-ray diffraction and is shown in Figure 1b.41 The cocrystal had a crystallographic structure adopting a centrosymmetric triclinic P1 space group with crystallographic cell parameters of a: 7.1123(2) A, b: 10.3751(3) A, c: 16.6615(3) A, a: 79.8437(14) , b: 86.524(2) , and g: 79.4256(13) . IND molecules formed a carboxylic acid dimer synthon centered at an inversion center, and the SAC molecules formed an imide dimer synthon. High-Shear Wet Granulation Table 1 shows the formulation of the materials for preparing granules and tablets. As negative controls in this study, references 1-2 (Refs 1-2) were performed without SAC. Runs 1-4 were carried out with all materials for build-in quality of the IND-SAC cocrystal. The ratio of IND:SAC was adjusted to 1:1 molar ratio in Runs 1-4. The demonstrated experimental conditions are summarized in Table 2. The additive rates were determined using the binding

̊

̊

solvent on account of a difference in volatility during high-shear granulation. As the binding solvent, water or ethanol were used. A small-scale high-shear granulator (55 mL) was used to prepare granules.29 Each powder fraction that passed through a 42-mesh (355 mm) powder screen was mixed in a granulator for 3 min with the formulation shown in Table 1. Granulation was carried out by kneading with adding a binding solvent for 10 min using syringe pump (Fusion 100; Chemyx, Stafford, TX) and mashing for 47 min at 30 C ± 1 C with 500 rpm of agitator rotational speed. Raman spectroscopy with MCR-ALS was performed during the granulation processes. After granulation, the obtained granules were dried at 60 C in a vacuum dryer at 40 C for 2 h, then the X-ray patterns and dissolution profiles of compressed tablets were measured. Raman Spectroscopy With MCR-ALS Analysis A Raman RXN1 analyzer with a PhAT probe head and a chargecoupled device detector (PhAT system analyzer, Kaiser, Lansing, MI) in backscattering mode was used to collect Raman spectra during granulation processes. The excitation laser wavelength and the

̊

Figure 2. Preprocessed Raman spectra of (a) Run 1 (IND g-form þ SAC þ H2O), (b) Run 2 (IND g-form þ SAC þ EtOH), (c) Run 3 (IND a-form þ SAC þ EtOH), and (d) Run 4 (IND AMS þ SAC þ EtOH). Red solid line and blue dotted line indicate 0 min and 60 min in the granulation process, respectively. The Raman peaks at (i-vi) are as described in the manuscript.

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output power were 785 nm and 20 mW, respectively. The spectral coverage was between 1660 and 1730 cm1 which was not affected by binding solvents, and Raman spectra were collected with exposed time of 20 s and cumulated with 1 measurement. HoloGRAMS software (Kaiser) was used for preliminary data processing. The Raman spectra of runs were analyzed by MCR-ALS analysis as a chemometrics method. MCR decomposes the experimental data matrix X (n  k) into the product of 2 smaller matrices C (n  m) and ST (m  k); thus, preprocessed Raman spectra were calculated in accordance with the following equations:

X ¼ CST þ E 0 B x11 B « @ xn1

/ 1 /

(1) 1 x1k C « C A ¼ xnk

0 B c11 B « @ cn1

/ 1 /

10 c1m C B s11 B « C A@ « cnm sm1

/ 1 /

1 s1k C « C A þ E smk (2)

Results Effect of the High-Shear Wet Granulation Process The reaction profile between materials during the high-shear wet granulation process was measured via Raman spectroscopy. Raman spectra of Refs 1-2 remained unchanged through the granulation process in both cases of adding water and ethanol as the binding solvent on account of the absence of SAC. This result indicated IND and other additives were unreactive with each other. Figure 2 represents the spectral changes in Raman spectra of Runs 1-4. All Raman spectra were preprocessed by standard normal variate and linear baseline correction and baseline offset. Before granulation, each Raman spectra has a particular peak related to the initial materials. The characteristic peaks at (i) 1696 cm1 in Runs 1-2, (ii) 1685 and (iii) 1675 cm1 in Run 3, and (iv) 1694 cm1 in Run 4 were attributed to benzoyl C10 ¼ O1 stretching vibration of the IND g-form, a-form, and AMS, respectively. IND a-form in Run 3

where C, ST, and E describe component concentration profiles, component spectra, and residual, respectively. The subscripts n, k, and m indicate the number of samples (spectra) according to different granulation times, spectral responses (intensities) according to different wavenumbers, and decomposed components, respectively. The number of components contributed to X and modeled by MCR have to be determined, and initial estimates for C and ST also have to be provided before the calculation. Then C and ST were optimized iteratively in an ALS algorithm until convergence was reached. More explanation has shown in previous reports.36,37,45 Unscrambler X was used as commercial multivariate data analysis software (version 10.5, CAMO software, Oslo, Norway). All the collected Raman spectra were preprocessed by standard normal variate, linear baseline correction and baseline offset before applying the spectra analysis. On the ground that the MCRALS method obtained a physically and chemically meaningful solution quantitatively, non-negative concentration and component spectra were used for calculation as the required defining constraints. The number of components was a priori decided on 4 components as in IND g-form, a-form, AMS, and final product with IND-SAC cocrystal.

X-ray Diffraction Measurement The X-ray diffraction (XRD) data of granules were collected using a X-ray diffractometer (RINT-Ultima III; Rigaku, Tokyo, Japan) with Cu Ka radiation (40 kV  40 mA). The diffraction angle range was from 5 to 35 in 2-theta with a step of 0.02 and scanned at 15 /min. Dried granule samples were prepared for XRD by grinding using hand grinding in an agate mortar.

Tableting and Dissolution Profile Measurements Flat-faced tablets were compressed with the granules at 100 MPa by compression pressure with a 200 mg weight and 8 mm in diameter using a single stroke tablet press (Handtab-100; Chihashi Seiki, Kyoto, Japan). Then, the tablet dissolution ability in 900 mL acidic aqueous solution as a test medium (pH 1.2 buffer; 37.5 ± 0.5 C) was measured using a USP dissolution test apparatus with a paddle speed of 100 rpm (DT-610, Jasco, Tokyo, Japan). The concentration with time of IND was determined using a UV/VIS spectrophotometer (V-530; Jasco, Tokyo, Japan) at 320 nm.

Figure 3. X-ray diffraction patterns of (a) materials and reference IND-SAC cocrystal (CC) and (b) dried samples after each granulation. The right blue areas show the INDSAC cocrystal characteristic peaks at 5.3 , 9.5 , 14.3 , 14.8 , and 24.5 of 2-theta.

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and attributed to the (110), (022), (21-2), and (130) diffraction planes, respectively. This indicated the reactions for cocrystals in Runs 2-4 were incomplete, and the cocrystal structure partly coexisted with the base materials still in the granules because the granulation process could not use many binding solvents to avoid excessive granulation. Raman Spectra Analysis by MCR-ALS

Figure 4. Calculated component spectra of IND a-form (component 1 [C1]; light red), cocrystal product (CP; component 2 [C2]; black), IND g-form (component 3 [C3]; red), and IND AMS (component 4 [C4]; blue) by MCR-ALS during Runs 2-4. The peaks at (ivi) are as described in the manuscript.

also had a peak at (iii) 1675 cm1 indicated a carbonyl C19 ¼ O4 stretching vibration. It should be noted that all runs spectra included a SAC peak at 1696 cm1 owing to C¼O stretching vibration. All Raman spectra except Run 1 were changed. In particular, the IND-SAC cocrystal peaks at (v) 1713 and (vi) 1680 cm1 assigned to carboxylic acid dimer C¼O stretching vibration and benzoyl C¼O stretching vibration, respectively, increased with Runs 2-4 processes using ethanol as a binding solution. When g-form was used as initial material in Runs 1-2, the ethanol was effective for cocrystal formation. In our system, both of IND and SAC had higher solubility in ethanol than water. There is a possibility that the used ethanol dissolved particle surfaces of cocrystal reactants and then led an intermediate phase which subsequently becomes a partly cocrystal and gradually disappears in the granulation process. This mechanism is similar to liquid-assisted grinding cocrystallization.46 On the other hand, it was revealed that water did not work as binding solvent for cocrystallization. One of the ratecontrolling factors to form cocrystal is dissolving rate of reactants in a solvent; thus, ethanol was better than water as binding solution for the granulation method. The phenomenon was also observed in Run 3 with a-form and Run 4 with AMS. It should be noted that the cocrystallization is not disturbed by water; the reaction may proceed if a large amount of solvent, even water, could be used.41 The reaction rate is depended on used solvent; the preformulation testing by evaporation method using various solvents is useful.41,43 However, the granulation should be carried out using green chemicals for pharmaceutical industry; therefore, water and ethanol are preferable and used in this study. Figure 3 shows the XRD pattern of each starting material, the reference IND-SAC cocrystal, and each dried granule sample using a one-step wet granulation method. IND-SAC cocrystal characteristic peaks which separated with other peaks were at 5.3 , 9.5 , 14.3 , 14.8 , and 24.5 of 2-theta and assigned to the (001), (011), (111), (01-2), and (1-21) diffraction planes, respectively. According to the result of XRD, the patterns of Refs 1-2 showed diffraction peaks owing to each crystal of IND and other additives. The granules by Run 1 also display no diffraction peaks of the cocrystal and seem corresponding to the mixture. These results of XRD corresponds with the results of Raman spectroscopy; thus, it was confirmed that cocrystal granules did not form in Refs 1-2 and Run 1. The granule XRD patterns of Runs 2-4 had peaks regarded as an IND-SAC cocrystals; however, they also had IND and SAC, which were initial materials peaks, such as at 11.7, 22.0 , 25.1, and 29.4 of 2-theta

The results of MCR-ALS in Runs 2-4 are shown in Figures 4 and 5. Refs 1-2 and Run 1 were not shown because these samples obviously did not provide cocrystal forms. As shown in Figure 4, collected Raman spectra were decomposed into 4 component spectra by MCR-ALS. The 4 component spectra could be assigned to IND g-form, a-form, AMS, and final product with IND-SAC cocrystal. The spectra of components 1-4 had specific Raman peaks at (ii) and (iii) for a-form, (v) and (vi) for the cocrystal product at 60 min, (i) gform, and (iv) AMS, respectively. Raman peaks at (i-vi) were assigned as in the above section; thus, standardized spectra were distinguished from each starting IND form in the Runs and the cocrystal product by MCR-ALS. Figure 5 shows the plots of calculated concentration of each component as a function of granulation time of Runs 2-4. The change in concentration indicated the reaction kinetics. All of the component 2 (cocrystal product)

Figure 5. Calculated concentration profiles of IND g-form (red crosses), IND a-form (light red rectangles), IND AMS (blue inverse triangles), and cocrystal product (CP, dark circles) as a function of granulation time by MCR-ALS during (a-c) Runs 2-4.

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intermediate phase at this time, and a partial reaction between IND and SAC subsequently proceeded even by the test medium. The INDs of Runs 2-4 were rapidly dissolved, and the dissolved concentration reached to approximately 0.23 mg/mL owing to forming cocrystal. It was confirmed that the Runs 2-4 granulation methods can contribute to the enhancement of IND solubility. Discussion

Figure 6. Integrated tablet dissolution profiles of Ref 1 (IND g-form þ H2O; green triangles), Ref 2 (IND g-form þ EtOH; dark circles), Run 1 (IND g-form þ SAC þ H2O; light blue diamonds), Run 2 (IND g-form þ SAC þ EtOH; red crosses), Run 3 (IND aform þ SAC þ EtOH; light red rectangles), and Run 4 (IND AMS þ SAC þ EtOH; blue inversed triangles).

concentration increased after each induction period while the others decreased with granulation time. Interestingly, each reaction profile seems to have a specific pattern to provide cocrystal formation. The fastest reaction kinetic reached greater than 95% of the reaction was Run 2, followed in order by Run 3 and Run 4. The details are considered in the discussion part. Dissolution Profile Figure 6 displays all the tablet dissolution profiles of Refs 1-2 and Runs 1-4. The dissolution rates and dissolved amounts of Refs 1-2 relatively lower than the other samples. According to the results of Raman spectra and XRD, the Run 1 sample was thought to show that the solubility had not enhanced; however, the tablet solubility was slightly better than Refs 1-2. The increase in the dissolution is owing to the presence of SAC in the tablet. Unlike the granulation method, the IND and SAC surfaces were eroded by the test medium when dissolution testing was implemented. The presence of SAC influenced that the particle surfaces may be transformed into an

In this part, the cocrystal formation kinetics is discussed with respect to the effect of the initial thermodynamic state of IND. The fraction cocrystallized as a function of time based on Raman studies with MCR-ALS during Runs 2-4 at 30 C is shown in Figure 5. Table 3 also shows the result of an r2 analysis of least-squares fit of various isothermal reaction models. Avrami-Erofeev model (A3) wellrepresented the kinetics of Runs 2-3. The kinetics of Run 4 was best fitted with the Ginstling-Brounshtein (D4) model. The A3 model stands for the random nucleation and growth process with 3dimensional growth of nuclei, whereas D4 indicates the model of 3-dimensional diffusion.47 Figure 7 represents least-squares fitting results of Runs 2-3, and Run 4 using the A3 and D4 model, respectively. The slope of the regression line corresponds to the reaction rate constant (k). The Raman peak at (i), which was attributed to a benzoyl C10 ¼ O1 stretching vibration of IND g-form, showed up and shifted with time during the first few minutes of Runs 3-4 granulations (Figs. 2c and 2d). In addition, dried granules of Runs 3-4 had XRD peaks at 11.7 and 29.4 , which corresponded to the diffraction planes at (110) and (130) of the g-form, although Runs 3-4 were composed without a g-form (Fig. 3). The crystal planes of (110) and (130) were almost parallel to the benzoyl group, and the structure gradually rearranged and transformed into the g-form as a stable state.48 These findings indicated the partly crystalline phase transition from a-form or AMS into g-form occurred along with cocrystallization in the first granulation under the influence of the solvent and mechanochemical energy owing to the agitation during the granulation. As shown in Figures 1b and 8a, both unit structures of INDSAC cocrystal and g-form are composed of similar conformation of IND-IND dimer via hydrogen bonding between carboxyl groups. Thus, it is considered that the dimer connection is the origination of the IND-SAC cocrystal formation, which is formed and grown with attaching SAC to the carboxyl groups of g-form IND as the nuclei of

Table 3 A r2 Analysis of Least-Squares Fitting Results Using Various Reaction Models to Describe Isothermal Cocrystallization Kinetics in the Wet Granulation Process Model

Nucleation Models Power law (P2) Power law (P3) Power law (P4) Avrami-Erofeev (A2) Avrami-Erofeev (A3) Prout-Tompkins (B1) Geometrical contraction models Contracting area (R2) Contracting volume (R3) Diffusion models 1-D diffusion (D1) 2-D diffusion (D2) 3-D diffusion-Jander (D3) Ginstling-Brounshtein (D4) Reaction-order models Zero-order (F0/R1) First-order (F1)

Integral Form g(x) ¼ kt

r2 Run 2

Run 3

Run 4

x1/2 x1/3 x1/4 [ln(1x)]1/2 [ln(1x)]1/3 ln[x/(1x)] þ Cx

0.9153 0.9334 0.9269 0.9579 0.9618 0.8727

0.8688 0.9050 0.9036 0.8963 0.9104 0.8839

0.8932 0.6426 0.6234 0.8616 0.8213 0.5115

1(1x)1/2 1(1x)1/3

0.9450 0.9370

0.8880 0.8749

0.8738 0.8964

x2 [(1x)ln(1x)] þ x [1(1x)1/3]2 1(2/3)x(1x)2/3

0.9153 0.8897 0.8289 0.8729

0.8688 0.8425 0.7703 0.8227

0.8932 0.9257 0.9127 0.9286

x ln(1x)

0.9507 0.9074

0.8695 0.8279

0.7765 0.9166

The value of x is the IND-SAC cocrystal product concentration (Fraction; x ¼ 0.050.95) from MCR-ALS shown in Figure 5.

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Figure 7. Plots of g(x) versus granulation time for Avrami-Erofeev model (A3; left) of (a) Run 2 (IND g-form þ SAC þ EtOH) and (b) Run 3 (IND a-form þ SAC þ EtOH), and Ginstling-Brounshtein model (D4; right) of (c) Run 4 (IND AMS þ SAC þ EtOH). The value of x is the crystal concentration (fraction; x ¼ 0.05-0.95) of the cocrystal product from MCR-ALS shown in Figure 5. The red crosses with dotted line, light red rectangles with solid line, and blue inversed triangles with broken line describe the curve fitting results of Run 2, Run 3, and Run 4, respectively.

the cocrystal. Additionally, the process of cocrystal formation is controlled by the nucleation process. The IND a-form reaction kinetics were slower than IND g-form although they fitted an A3 model. Figure 8 shows both chemical structures. IND a-form is known as a metastable form, and its solubility is higher than IND g-form (solubility ratio; a/g 1.1).49 However, the a-form was composed of 3 independent molecules, namely the a-form has a larger steric effect than the g-form. In addition, the a-form has a carboxyl-carboxyl dimer synthon, in which the intermolecular distances of one side were 1.638 Å, whereas the distance for the g-form and IND-SAC cocrystal were 1.748 Å and 1.699 Å, respectively (Figs. 8a and 1b). This indicated that the a-form is more nonresponsive to cocrystallization on account of shorter intermolecular distances and stronger bonds than the g-form and cocrystal. The steric effects and intermolecular forces may be valid for these granulation methods. Crystallite sizes in granules of Runs 2-4 were calculated from the result of XRD using the Scherrer equation:

Dhkl ¼

Kl ðBhkl cos qÞ

(3)

where Dhkl is the crystallite size, hkl is the Miller index, K is the crystallite shape factor (generally 0.9), l is the wavelength of Xrays, and B is the width (full-width at half-maximum).50 The crystallite size in granules in Run 2-4 were 36.3 nm, 55.6 nm, and 102.6 nm, respectively. Generally speaking, crystalline kinetics is consisted of nucleation and crystal growth, and nucleation rate is exponentially altered as a function of Gibbs free-energy change and critical radius of nuclei.51,52 This theory is explained Boltzmann distribution, a number of crystal embryos and nuclei appear when critical nucleus size is small. Therefore, it was assumed that in case of Runs 2-3, larger number of crystal nuclei were presented or formed than that of Run 4 and resulted to provide small crystals based on A3 model with random nucleation and growth. On the other hands, in the case of Run 4, the small number of nuclei resulted to produce larger crystal by 3-dimensional diffusion. Because the AMS is in the thermodynamically unstable state and the solid density is lower than that of crystal, the cocrystal formation with AMS can be corresponded to 3-dimensional diffusion

Figure 8. The crystalline structure of (a) IND g-form and (b) IND a-form. The light blue broken lines and green values indicate the hydrogen bonding and distance in Å between atoms, respectively.

D4 model. In summary, the reaction kinetics were individually depending on the initial thermodynamic state of IND. Conclusion This study presented widely reported IND-SAC cocrystals to enhance the solubility of IND, as a BCS class II drug, and were demonstrated regarding the kinetics using a high-shear wet granulation method with Raman spectroscopy. The in situ Raman spectra measurements displayed the cocrystal formation process. Raman spectra of granulation using water did not change during the processes (Run 1). On the other hand, the Raman peaks corresponded IND-SAC cocrystals increased during granulation using ethanol (Runs 2-4). Both of IND and SAC have higher solubility in ethanol; particle surfaces dissolved and became the intermediate phase during granulation with ethanol and formed cocrystals by interaction at the interface between particles of IND and SAC. Additionally,

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the reaction kinetics in the granulation process was distinguished by best fitted reaction models. The kinetics variance among the granulation methods depended on the initial material states of IND solids because they had a different crystal structure, thermodynamic state, interaction, and crystallization mechanism for the cocrystal. The obtained final products using ethanol in the granulation process were confirmed as forming part of the IND-SAC cocrystal and improving the solubility from the results of XRD and dissolution testing. These scalable methods which can reduce the number of unit operations are required in the pharmaceutical industry. Acknowledgments The authors are grateful to S.T. Japan (Tokyo, Japan) for providing a PhAT system analyzer. Dr. Raj Suryanarayanan and Dr. Naga Kiran Duggirala gave us constructive comments and supports. The work was supported by Grant-in-Aid for JSPS Fellows (Grant Number JP19J15135) and JSPS Overseas Challenge Program for Young Researchers. References €s H, Shah VP, Crison JR. A theoretical basis for a bio1. Amidon GL, Lennerna pharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413-420. 2. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 2000;88(10): 1058-1066. 3. Ku MS, Dulin W. A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept. Pharm Dev Technol. 2012;17(3):285-302. 4. Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420(1):1-10. 5. Aitipamula S, Banerjee R, Bansal AK, et al. Polymorphs, salts, and cocrystals: what’s in a name? Cryst Growth Des. 2012;12(5):2147-2152. € Zaworotko MJ. Pharmaceutical cocrystals: 6. Duggirala NK, Perry ML, Almarsson O, along the path to improved medicines. Chem Commun. 2016;52(4):640-655. 7. Khankari RK, Grant DJW. Pharmaceutical hydrates. Thermochim Acta. 1995;248: 61-79. 8. Brittain HG, Grant DJW. Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In: Brittain HG, ed. New York: Marcel Dekker; 1999. 9. Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603-616. 10. Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des. 2011;11(7):2662-2679. 11. Vippagunta SR, Brittain HG, Grant DJW. Crystalline solids. Adv Drug Deliv Rev. 2001;48(1):3-26. 12. Porter III WW, Elie SC, Matzger AJ. Polymorphism in carbamazepine cocrystals. Cryst Growth Des. 2008;8(1):14-16. 13. Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J Pharm Sci. 2002;91(8):1863-1872. €bmann K, Laitinen R, Grohganz H, Gordon KC, Strachan C, Rades T. Coa14. Lo morphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. Mol Pharm. 2011;8(5):1919-1928. 15. Food and Drug Administration. Regulatory Classification of Pharmaceutical Cocrystals Guidance for Industry. MD: Silver Spring; 2018. Available at: https:// www.fda.gov/media/81824/download. Accessed February 20, 2019. 16. Jones W, Motherwell WDS, Trask AV. Pharmaceutical cocrystals: an emerging approach to physical property enhancement. MRS Bull. 2006;31(11):875-879. 17. Martin FA, Pop MM, Borodi G, Filip X, Kacso I. Ketoconazole salt and Co-crystals with enhanced aqueous solubility. Cryst Growth Des. 2013;13(10):4295-4304. 18. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech. 2011;12(2):693-704. n L, Laity PR, Day GM, Jones W. Improving mechanical 19. Karki S, Fris ci c T, F abia properties of crystalline solids by cocrystal formation: new compressible forms of Paracetamol. Adv Mater. 2009;21(38-39):3905-3909. 20. McNamara DP, Childs SL, Giordano J, et al. Use of a Glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res. 2006;23(8): 1888-1897. 21. Zhang GGZ, Henry RF, Borchardt TB, Lou X. Efficient Co-crystal screening using solution-mediated phase transformation. J Pharm Sci. 2007;96(5):990-995. 22. Hattori Y, Sato M, Otsuka M. Initial dissolution kinetics of cocrystal of carbamazepine with nicotinamide. J Pharm Pharmacol. 2015;67(11):1512-1518.

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