Using Dissolution and Pharmacokinetics Studies of Crystal Form to

Nov 1, 2013 - The crystal engineering strategy was used to facilitate the supramolecular synthesis of a new crystalline phase of iloperidone, an atypi...
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Using Dissolution and Pharmacokinetics Studies of Crystal Form to Optimize the Original Iloperidone Tingting Zhang,†,# Yan Yang,§,⊥,∥,# Haitao Wang,† Fuxing Sun,‡ Xiaojun Zhao,‡ Jiangtiao Jia,‡ Jingrui Liu,§ Wei Guo,§ Xiaoqiang Cui,*,† Jingkai Gu,*,§,⊥,∥ and Guangshan Zhu*,‡ †

Department of Materials Science, Key Laboratory of Automobile Materials of MOE and State Key Laboratory of Superhard Materials, Jilin University, Changchun, 130012, P. R. China ‡ State Key Laboratory of Inorganic Synthesis & Preparative Chemistry, Jilin University, Changchun 130012, China § Research Center for Drug Metabolism, Jilin University, Changchun 130012, P. R. China ⊥ National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, P. R. China ∥ Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin Province, Changchun 130012, P. R. China S Supporting Information *

ABSTRACT: The crystal engineering strategy was used to facilitate the supramolecular synthesis of a new crystalline phase of iloperidone, an atypical psychotropic drug with known problems related to poor dissolution and absorption profile. The novel crystal forms Jilin University China-Cocrystal-1 (JUC-C1), Jilin University China-Cocrystal-2 (JUC-C2), and Jilin University China-Cocrystal-3 (JUC-C3) of iloperidone with 3-hydroxybenzoic acid (3-HBA), 2,3-dihydroxybenzoic acid (2,3-DHBA), and 3,5-dihydroxybenzoic acid (3,5-DHBA) were obtained using the reaction crystallization method (RCM). The dissolution and pharmacokinetics studies were performed to exploit this atypical psychotropic drug. In the dissolution experiment, JUCC1, JUC-C2, and JUC-C3 (JUC-C1−3) showed a much faster dissolution rate than the original active pharmaceutical ingredient (API) in simulated gastric fluid media (pH = 1.2). Furthermore, pharmacokinetic behavior of JUC-C1−3 and API was investigated to evaluate the effectiveness of this strategy for enhancing the oral absorption of iloperidone. The in vitro and in vivo studies revealed that JUC-C2 possessed an excellent dissolution behavior and improved pharmacokinetic profile.

1. INTRODUCTION The synthesis of cocrystals has gained much attention in recent years due to its wide application in modifying the physicochemical and biological properties of active pharmaceutical ingredients (APIs).1 Generally, a pharmaceutical cocrystal with a specific biological target is being investigated extensively as it could solve the problems encountered in the use of solid APIs.2 In this respect, one typical example is lamotrigine reported by Zaworotko and co-workers who synthetized two lamotrigine cocrystals with improved solubility in the aqueous media and acidified aqueous media, respectively.3 In addition, Bak et al. constructed an AMG 517-sorbic acid cocrystal with a much better aqueous solubility than the AMG 517 free base.4 The methods of crystal engineering could offer a flexible approach by introducing another molecular component into the crystal lattice, making it possible to establish the linkage with the cocrystal formers (CCF) which are included in the pharmaceutically acceptable formers list,1c such as the Generally Regarded as Safe (GRAS) list and Everything Added to Food in the United States (EAFUS) list. Generally, H-bonds and π−π interactions are formed between the API and CCF to construct © 2013 American Chemical Society

a supramolecular synthon. Statistical studies of X-ray crystal structures in the Cambridge Structural Database (CSD) have provided commonly occurring H-bonding motifs, and thus the information could be used to predict the cocrystal structures and direct the synthesis.5 Our group has been working on the design and synthesis of crystals, such as the Jilin University China compounds (JUCs).6 In this research, iloperidone, which is a second-generation antipsychotic agent approved by the U. S. Food and Drug Administration (FDA) in 2009 for the treatment of schizophrenia in adults,7 was selected to exploit its novel crystal forms with excellent physicochemical and biological properties. Commercial tablets (FANAPT) are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. Chemically, there are five types of H-bond acceptors, two N atoms and three O atoms, which are probable of forming hydrogen bonds with the other formers (Scheme 1). Biologically, Received: July 5, 2013 Revised: October 22, 2013 Published: November 1, 2013 5261

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Scheme 1. Molecular Structures of API and CCF

2.3.2. PXRD. Crystal was characterized by a Scintag X1 diffractometer with Cu Kα (λ = 1.5418 Å) at 40 kV, 35 mA. Data were collected over an angular range of 4−40° 2θ value in continuous scan mode using a step size of 0.05° 2θ value and a scan speed of 1.0°/min. 2.3.3. Elemental Analysis. Elemental analyses (C, H, and N) were carried out on a Perkin-Elmer 240 analyzer. 2.3.4. Liquid Chromatography−Tandem Mass Spectrometry (LC−MS/MS) Analysis. Analysis was performed on a LC−MS/MS system comprising Agilent 1100 Series HPLC system (Agilent Technologies, Palo Alto, CA, USA) and API 4000 mass spectrometer (Applied Biosystems MDS Sciex, Ontario, Canada). Chromatographic separation was achieved using an HC-C18 column (150 mm × 4.6 mm I.D., 5 μm particle size, Agilent Technologies) at 40 °C with a mobile phase of acetonitrile/ammonium acetate (10 mM) (85:15, v/v), at 1 mL/min. Analysis was carried out with an electrospray ionization (ESI) source using positive ion (ESI+) mode. The instrument parameter settings were as follows: ionspray voltage (IS) 5000 V, declustering potential (DP) 90 V, collision energy (CE) 38 eV, collision cell exit potential (CXP) 10 V, channel electron multiplier (CEM) 2300 V, nitrogen curtain gas 15 psi, gas 1 (GS1) and gas 2 (GS2) at 50 and 40 psi, source temperature 450 °C, and dwell time 200 ms. The detector was operated under multiple reaction monitoring (MRM) mode monitoring the precursor to product ion transitions for iloperidone from m/z 427.3 to m/z 261.1, and for isobutyl carbonate ester of paliperidone (I.S.) from m/z 527.2 to m/z 307.1. Data were acquired using Analyst Software 1.4.2 (Applied Biosystems MDS Sciex, Ontario, Canada). 2.4. Dissolution Study. Dissolution studies of accurately weighed JUC-C1−3 containing an equal amount of 4 mg of iloperidone and 4 mg of API were carried out on ZRS-8G Dissolution Tester from Tianda Tianfa Technology Co., Ltd, respectively. According to the apparatus of dissolution test in USP32 and the solubility in HCl solution (pH 1.2) of about 3.9 mg/mL,13 the basket method was used to determine the dissolution profile of JUC-C1−3 and the original API at 37 ± 0.5 °C under sink condition with 500 mL HCl solution (pH 1.2) as the dissolution medium to simulate succus gastricus. The basket was continuously rotated at 50 rpm, and 10 mL of dissolution samples was successively collected from the dissolution medium at 0, 10, 20, 30, 45, 60, 90, and 120 min and immediately replaced with an equal volume of fresh medium. The resulting solution was filtered with 0.45 μm membrane filters to remove the insoluble materials and further diluted with mobile phase prior to LC−MS/MS analysis. 2.5. Pharmacokinetics Study. The pharmacokinetics of JUCC1−3 and the original API were conducted using Beagle dogs. After an overnight fast, 12 male Beagle dogs were randomly divided into four groups before dosing. 35 mL of HCl-KCl buffer (0.1 mol/L) was administered orally at 15 min before the dosage form to normalize the stomach pH variability of Beagle dogs.14 A gelatin capsule containing 4 mg API without any excipients/additives was orally administered to Beagle dogs in group 1. Beagle dogs in group 2−4 were each given a gelatin capsule containing JUC-C1, JUC-C2, or JUC-C3 equivalent to 4 mg of iloperidone without any excipients/additives. Blood samples

iloperidone is classified in the Class II category (low solubility and high permeability) according to the Biopharmaceutics Classification System (BCS),8 which is practically insoluble in water (0.012 mg/mL).9 Oral bioavailability of iloperidone was JUC-C1 > API. This phenomenon could be attributed to the improved physicochemical properties of those cocrystals. This observation suggested that JUC-C1−3 with an enhanced dissolution rate would potentially favorably affect the gastrointestinal (GI) absorption and onset action of iloperidone. 3.3. PK Study. The PK study of JUC-C1−3 and the original API was carried out in Beagle dogs, which is the classic model for the evaluation of absorption. Mean plasma concentration− time profiles for iloperidone after oral administration are shown in Figure 6. The PK parameters presented in Table 3 were calculated with Drug and Statistics 3.0. The results indicated that the oral administration of JUC-C2 produced higher oral bioavailability compared to the others throughout a 12 h period, which was compatible with the dramatically enhanced release in the dissolution test. Taking the AUC0‑∞ (2.56 ng × h/mL) of API as 100%, the relative bioavailability of JUC-C1, JUC-C2, and JUC-C3 was calculated at 9.77%, 223%, and 99.4%, respectively. Compared with other types of cocrystals, the absorption of JUC-C2 was the best. Notably, the bioavailability of JUC-C2 was enhanced by more than two times, indicating a very significant improvement. The AUC0‑∞ and Cmax values of JUC-C2 were approximately 2.2-fold and 3.9-fold greater than that of API, respectively, which was probably due to the excellent dissolution behavior of iloperidone in JUC-C2. JUC-C2 was effective in improving the absorption and oral bioavailability of iloperidone. In addition,

Figure 2. Hydrogen bonding pattern in the corresponding carboxylic acid. The wave chains form between the corresponding carboxylic acid and H2O through O−H···O H-bonds. The chains of 3-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, and 3,5-dihydroxybenzoic acid are presented respectively in (a), (b), and (c).

the plasma concentration of JUC-C2 reached to the maximum concentration and effective blood level earlier after oral administration, which suggested that JUC-C2 exhibited a more rapid absorption profile of iloperidone and could thus achieve a rapid onset of action. Although the enhancement in dissolution behavior of JUC-C1−3 was demonstrated in dissolution experiments, PK properties of the cocrystal forms were similar (JUC-C3) or even 5264

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Figure 3. Crystal packing in iloperidone molecules. (a) Notice the “W” wavelike structure along the b-axis, similar to that seen in both JUC-C2 and JUC-C3 to show one-dimensional (1D) chains. (b) Packing diagram for (a) showing two layers formed by the close packed tetramers.

Figure 4. The PXRD patterns of the experimental and simulated one: (a) JUC-C1, (b) JUC-C2, and (c) JUC-C3.

Figure 5. Dissolution profiles in simulated gastric fluid media for the API and JUC-C1−3.

Figure 6. Mean plasma concentration−time profiles of API and JUCC1−3 in Beagle dogs after oral administration.

worse (JUC-C1) compared to API, indicating that the rest of the hydroxyl of aromatic ring might lead to desirable physicochemical properties of crystal forms, and its location played a critical role in their biological properties. In addition, the absorption of drugs involved several different processes. The dissolution study was still insufficient to accurately reflect the complex in vivo situation, such as physiological factors, complex binding, and potential biotransformation, all of which should be considered as possible factors. The additives in JUC-C1−3 could also influence the GI fluid pH, viscosity, and the rate of gastric emptying resulting in the alteration of PK profile. On the other hand, iloperidone was extensively metabolized by the cytochrome P450 enzyme involving CYP2D6 and

CYP3A4.7a,c,15 The coadministration of iloperidone with additives potentially increase/decrease systemic exposure due to the effect on CYP2D6 and CYP3A4, which might possibly contribute to the differences of JUC-C1−3 in bioavailability.

4. CONCLUSIONS In summary, our work was targeted for the development of novel crystal forms with improved dissolution and PK performance. The three resulting pharmaceutical cocrystals of iloperidone with the corresponding carboxylic acid were designed and synthesized through crystal engineering. Single crystal X-ray diffraction confirmed that the cocrystals with a branched network in the supramolecular synthon were formed. 5265

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Table 3. PK Data of the Original API and JUC-C1−3 drug original API JUC-C1 JUC-C2 JUC-C3

Cmax, ng/mL 0.45 0.12 1.77 1.40

± ± ± ±

0.02 0.02 0.29 0.18

Tmax, h 4.00 2.33 1.17 2.00

± ± ± ±

t1/2, h

0.00 0.55 0.29 0.50

4.63 2.70 6.40 1.42

ASSOCIATED CONTENT

S Supporting Information *

Characterization results of iloperidone crystal forms; thermogravimetric analysis (TGA) curves collected on a Perkin-Elmer TGA 7 thermogravimetric analyzer with a heating rate of 10 °C/min at air for original API and the crystal forms in the temperature range 10−800 °C. FT-IR spectrometer using KBr disks dispersed with sample powders in the 4000−400 cm−1 range. The branched structures of JUC-C2 and JUC-C3. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*(X.Q.C.) E-mail: [email protected]. *(J.K.G.) E-mail: [email protected]. *(G.S.Z.) E-mail: [email protected]. Author Contributions #

These authors contributed equally to the work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support of the National Natural Science Foundation of China (Nos. 21075051, 21275064, 30973587, and 81102383), Program for New Century Excellent Talents in University (NCET-10-0433), the National Basic Research Program of China (973 Program, No. 2012CB821700), Major International (Regional) Joint Research Project of NSFC (No. 21120102034) and NSFC (No. 20831002).

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1.10 1.53 0.60 0.11

AUC0‑∞, ng·h/mL

F, %

± ± ± ±

100 9.77 223 99.4

2.56 0.25 5.71 2.39

0.10 0.06 1.52 0.39

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The dissolution profiles of JUC-C1−3 were greatly improved compared to the original API in simulated gastric fluid. In the following in vivo study, JUC-C2 possessed a favorable PK profile after the oral administration, which was consistent with the markedly increased dissolution rate. The great improvement of absorption illustrated that JUC-C2 with the most rapid dissolution rate and the highest in vivo exposure following oral administration would be a favored candidate for the pharmaceutical industry. In addition, toxicity and efficacy studies are still underway in our laboratory.

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dx.doi.org/10.1021/cg4010104 | Cryst. Growth Des. 2013, 13, 5261−5266