Coamorphous Lurasidone HydrochlorideâSaccharin with Charge

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Coamorphous Lurasidone Hydrochloride-Saccharin with Chargeassisted Hydrogen Bonding Interaction Shows Improved Physical Stability and Enhanced Dissolution with pH-independent Solubility Behavior Shuai Qian, Weili Heng, Yuanfeng Wei, Jianjun Zhang, and Yuan Gao Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00349 • Publication Date (Web): 22 Apr 2015 Downloaded from http://pubs.acs.org on April 28, 2015

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Crystal Growth & Design

Coamorphous Lurasidone Hydrochloride−Saccharin with Charge-assisted Hydrogen Bonding Interaction Shows Improved Physical Stability and Enhanced Dissolution with pH-independent Solubility Behavior Shuai Qian #,†, Weili Heng #,†, Yuanfeng Wei †, Jianjun Zhang *,‡, Yuan Gao †

†

School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, 210009,

P.R. China ‡

School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, P.R. China

ABSTRACT: Recently, coamorphous systems composed of a drug and a guest molecule, have gained increasing interest, due to their ability to overcome limitations associated with amorphous drug alone. In this study, a single-phase coamorphous form of lurasidone hydrochloride (LH) (a water-insoluble atypical antipsychotic agent with pH-dependent solubility) with saccharin (SAC) in a 1:1 molar ratio was obtained, and characterised by DSC and XPRD. Peak shifts in the FTIR spectra indicated the formation of charge-assisted hydrogen bond between the N+-H group of LH and the C=O group of SAC. In comparison to crystalline LH, amorphous LH showed similar solubility and temporary improvement in the intrinsic dissolution rate and supersaturated 1

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dissolution, while coamorphous LH-SAC exhibited greatly improved solubility with pH-independent solubility behavior in pH range of 2 to 5.5, as well as persistent enhanced intrinsic dissolution rate and supersaturated dissolution. In addition, coamorphous LH-SAC showed superior physical stability than amorphous LH under long-term storage condition. The coamorphization effect and charge-assisted hydrogen bond in coamorphous LH-SAC were speculated to be responsible for the above phenomena by prohibiting the recrystallization of LH.

2


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1.

INTRODUCTION

With more than 40% of new chemical entities are regarded as poorly soluble in water, which are associated with various formulation-related performance issues, improving the bioavailability of these drugs by solubility/dissolution enhancement has become crucial for pharmaceutical companies seeking to bring efficacious drugs to patients in reasonable dosing regimens.

1

The

amorphous system, a solid state with no long-range order molecular packing, is considered to be a promising approach to improve the solubility/dissolution rate and hence bioavailability/drug efficacy for Biopharmaceutics Classification System (BCS) class II and IV drugs. However, inherent poor physical stability due to higher energy state, and the subsequent risk of devitrification during manufacturing, storage and dissolution, have greatly restricted the application of amorphous system in drug development. 2 To improve the physical stability of amorphous drugs under storage and dissolution conditions, polymers with high glass transition temperature (Tg) were employed to form solid dispersions with drug molecules. The increased Tg of this amorphous system and hence reduced mobility would increase the physical stability of the amorphous drugs. intermolecular

interactions

between

drugs

and

water-soluble

3

In addition,

polymers

(e.g.

indomethacin-polyvinyl pyrrolidone and celecoxib-polyvinyl pyrrolidone solid dispersions) could further stabilize the amorphous state of solid dispersion by reducing the molecular mobility of drugs and thus their ability to nucleate and crystallize.

4-6

However, when drugs are

poorly miscible with polymeric carriers, in order to incorporate a therapeutic drug dose into the solid dispersion system, usage of large quantities of polymers would be inevitable, which would 3



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lead to a high polymer:drug ratio and subsequently large bulk volume/mass of final dosage forms. 7

Furthermore, a large quantity of water-soluble polymers used in solid dispersion could absorb

moisture easily, which would facilitate the recrystallization of the incorporated amorphous drugs. 8

In view of the effect of intermolecular interactions between drugs and polymers on the stability of amorphous systems, a concept of coamorphous binary systems combining two drugs or a drug with a small molecular excipient has recently been introduced and proved to be an interesting alternative to drug-polymer solid dispersions by overcoming the limitations of solid dispersions. 9 For drug-drug combination, coamorphous mixtures of indomethacin and ranitidine hydrochloride,

10

cimetidine and indomethacin,

11

naproxen and indomethacin 9 and simvastatin

and glipizide

12

demonstrated significant enhancement in solubility/dissolution rate and/or

physical stability in comparison to the pure amorphous forms and/or amorphous physical mixtures. However, the potential in vivo drug-drug interactions including pharmacokinetic and pharmacodynamic behaviors should be considered, which are crucial to the drug efficacy and side effects. For example, cimetidine and indomethacin shared the same metabolic enzyme CYP2C9 and would likely alter the metabolic profiles of each other. 13, 14 Therefore, considering that more clinical evidences are needed to prove the efficacy and safety of combination use of drugs due to the frequently occurred drug-drug interaction, coamorphous binary system combining a drug with a small molecular excipient seems to be a more promising alternative to stabilize amorphous drugs. Gao et al. (2013) showed that coamorphous repaglinide-saccharin increased solubility and dissolution rate of repaglinide in various media as well as its physical 4


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stability. The hydrogen bonding between repaglinide and saccharin was proposed to be the main factor that strengthened the linkage between two components, which prevented the conversion of amorphous repaglinide into crystalline state. 15 Lurasidone hydrochloride (LH, Figure 1a) is an atypical antipsychotropic agent for the treatment of schizophrenia and bipolar disorder. Clinical evidences showed that LH had a more significant efficacy in treating the psychopaths with cognitive impairment than other commercial available antipsychotics.

16

As a BCS class II drug 17, LH has poor bioavailability with absolute

oral bioavailability of 9-19% in human 18 and ~23% in rats 19. In addition to extensive first-pass metabolism (only 1% of unchanged lurasidone was recovered in urinary and biliary routes after intravenous administration of LH

19

), incomplete absorption of LH due to poor water solubility

and low dissolution is the major reason for its low oral bioavailability (low urinary recovery (9%) but high fecal recovery (80%) of radiolabeled LH after oral administration 20). In our preliminary study, in addition to the poor aqueous solubility, LH showed a pH-dependent solubility profile in the pH range of 2 to 6.8 with the maximum solubility at pH 3.8. However, pH-dependent solubility would raise the possibility of pH-dependent exposure of compounds, the oral bioavailabilities of which tend to be affected by the physiological conditions of patient (e.g. fed or fast, gastric emptying time), and hence possibly resulting in inconsistent clinical efficacy with large variability.

21, 22

Thereby, increasing the aqueous solubility and overcoming such

pH-dependent solubility behavior of LH would definitely benefit its in vivo performance. In the current study, coamorphous drug-excipient combination of LH and saccharin (SAC, Figure 1b) was investigated. As an acidic salt formed by hydrochloride acid and weak base 5



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lurasidone, LH provides two carbonyl groups (hydrogen acceptor) and a charge-assisted secondary amine (N+-H) group (hydrogen donor) (Figure 1a).

23

SAC, a FDA approved

sweetener, was selected for the preparation of coamorphous combination due to its special chemical structure with both hydrogen donor and acceptor. In this study, we reported a novel preparation of coamorphous LH-SAC with an uncommon intermolecular hydrogen bond, the charge-assisted hydrogen bond, in order to enhance the solubility along with less pH dependence, dissolution rate of LH, as well as the physical stability of amorphous LH. The physiochemical properties of the prepared coamorphous LH-SAC, including thermal property, structure property, molecular interaction, dissolution and physical stability, were characterized in comparison to the amorphous and crystalline LH.

2.

EXPERIMENTAL SECTION

2.1. Materials Lurasidone hydrochloride (LH, M = 529.1 g·mol-1) was synthesized and gifted by Changzhou Yinsheng Pharmaceutical Co., Ltd (Changzhou, China). Lurasidone base was prepared by stoichiometry titration with sodium hydroxide. Saccharin (SAC, M = 183.2 g.mol-1) was purchased from Tianjin Guangfu Fine Chemical Research Institute (Tianjin, China). Methanol of HPLC grade was purchased from E. Merk (Darmstadt, Germany). All other chemical reagents were obtained from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China).

2.2. Methods 6


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2.2.1. Preparation of amorphous LH and coamorphous LH-SAC LH (500 mg, 0.945 mol) was dissolved in 50 mL of methanol at room temperature, followed by rotary vacuum evaporation at 55 ºC. The solid residue in the flask was collected and vacuum dried for 24 h at room temperature to remove the residual solvent. Coamorphous LH-SAC was prepared using the same procedure after dissolving 500 mg (0.945 mol) of LH and 173.1 mg (0.945 mol) of SAC in 50 mL of methanol. The obtained amorphous LH and coamorphous LH-SAC were sieved through 100 mesh (150 µm) and stored in a vacuum desiccator over anhydrous calcium chloride at 4 ºC for further characterization.

2.2.2. Solid state characterization X-ray Powder Diffraction (XRPD) was performed at ambient temperature using a thermo X’TRA X-ray Power Diffratometer (Thermo Fisher Scientific Inc., USA) with a Cu-Kα radiation (λ=1.5406 Å) source. The samples were gently placed in an aluminum holder. The tube voltage and amperage were set at 40 kV and 40 mA, respectively. For each sample, XRPD pattern was collected from 2θ of 3° to 60° with a scanning speed of 10 °/min and a step size of 0.02°. Differential scanning calorimetry (DSC) was carried out using a Pyris 1 DSC (PerKinElmer, USA). The temperature and cell constants were calibrated using indium. Samples of about 3-5 mg crimped in a non-hermetic aluminum DSC pan were heated from -5 to 300 °C at a heating rate of 10 °C/min. The glass transition temperature was analyzed using NETZSCH-Proteus software (version 4.2). A Nicolet Impact 410 FT-IR Spectrophotometer (Thermo Fisher Scientific Inc., Waltham, 7



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MA, USA) was employed in KBr diffuse reflectance mode for recording the IR spectra of samples. 2 mg of each sample was mixed with 200 mg KBr and compressed into tablets. A total of 64 scans were performed (with a spectral resolution of 4 cm-1) over the range of 400-4000 cm-1. pKa value of lurasidone was calculated by the Chemaxon software (Version 6.2, ChemAxon Ltd., Budapest, Hungary).

2.2.3. Stoichiometry determination of components The stoichiometry relationship between LH and SAC in the coamorphous system was determined. Sample solution was prepared by transferring the equivalent of 10 mg of LH into a 25 mL volumetric flask and then dissolving with mobile phase. LH and SAC were assayed by HPLC after filtration and 10-fold dilution. Samples were analyzed in triplicate. An accurate and precise HPLC method was established to determine the concentration of LH and SAC in samples using a reversed phase Shimadzu LC-2010AHT HPLC system (Shimadzu Corporation, Kyoto, JP). LH and SAC were simultaneously separated by an Inertsil ODS-SP column (150×4.6 mm, 5 µm) and detected at 230 nm. Mobile phase consisting of acetonitrile and water containing 0.05% triethylamine and 0.05% acetic acid (70/30, v/v) was run at 1.0 mL/min. The column temperature was set at 30 °C.

2.2.4. Solubility determination The glass vial containing excess solid powders (crystalline LH, amorphous LH, physical mixture 8


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of crystalline LH and SAC (1:1 mole ratio), physical mixture of amorphous LH and crystalline SAC (1:1 mole ratio) or coamorphous LH-SAC) and 10 mL of 0.05 M phosphate buffer solutions (PBS, pH 2.0, 3.0, 3.8, 4.5, 5.0, 5.5, 6.0 and 6.8) was placed in a water bath and stirred with a magnetic bar. After stirring for 24 h at 25 °C, the slurry was filtered through a 0.22 µm nylon filter (Millipore, Bedford, MA) (24 hours was enough to reach the solubility equilibrium, data not shown). The concentrations of LH in the obtained filtrates were analyzed by above HPLC/UV method after appropriate dilution. Each experiment was repeated in triplicate.

2.2.5. Intrinsic dissolution testing For intrinsic dissolution rate (IDR) studies, 150 mg of crystalline LH, amorphous LH or coamorphous LH-SAC was compressed at a pressure of 115.2 MPa for 10 s using a hydraulic press (Jintan Ruiding Machinery Co., Ltd. Changzhou, China). The resulting discs with a surface area of 0.5024 cm2 were inserted into a PTFE intrinsic dissolution sample holder to obtain a flat surface, eventually only one surface of each tablet was exposed to the dissolution medium. USP II dissolution apparatus was applied in the intrinsic dissolution study. Dissolution tests (six replicates) were performed in 900 mL of 0.2 M PBS 3.8 at 37 ºC with the paddle rotating speed of 50 rpm. 3 mL of aliquots were withdrawn at the predetermined time points (5, 10, 15, 20, 40, 60 and 90 min) and analyzed by above HPLC/UV method. To evaluate IDR of LH, the cumulative amount dissolved per surface unit of the compact was plotted against time. The slope of the linear region (r2 ≥ 0.95) was taken as the intrinsic dissolution rate. 24, 25

9



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2.2.6. Dissolution under supersaturated conditions Supersaturated dissolution testing (six replicates) was conducted using a small-volume dissolution apparatus (RC-806 dissolution tester, TDTF technology Co., Ltd, China) by a paddle method as described in other report.

26

In brief, the dissolution studies were conducted in 200

mL of dissolution media (0.2 M HCl and 0.2 M PBS pH 3.8) with a rotation speed of 50 rpm at 25 °C. After adding the testing powders (crystalline LH, amorphous LH or coamorphous LH-SAC, equivalent of 500 mg LH) to dissolution media, 2 mL of samples were withdrawn and filtered at predetermined time points (0.5, 1, 2, 4, 7, 10 and 24 h). LH concentration was analyzed by the HPLC/UV method described above.

2.2.7. Physical stability of amorphous LH and coamorphous LH-SAC Amorphous LH and coamorphous LH-SAC powders were exposed in a constant temperature/ humidity chamber (Shanghai Boxun Industry & Commerce Co., Ltd., Shanghai, China) with 25 ºC/60% RH (long-term storage condition). Samples were collected at predetermined time to investigate the stability of amorphous materials by XRPD up to 60 days.

2.2.8. Data analysis All results were expressed as mean ± S.D. Statistical data analyses were performed using one-way analysis of variance (ANOVA) with p < 0.05 as the minimal level of significance.

3. RESULTS AND DISCUSSION 10


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3.1. Stoichiometry of 1:1 of coamorphous LH-SAC The stoichiometry of coamorphous LH-SAC was determined by the validated HPLC method. LH (retention time of 7.4 min) was separated well from SAC (retention time ~ 1.1 min) with a resolution of 9.18. Within the linear concentration range (20.24-80.96 µg·mL-1 for LH and 0.1-8.0 µg·mL-1 for SAC), good linearity (r2 >0.9998) was achieved. LH and SAC solutions were found to be stable for at least 24 h. The relative standard deviations (RSD) of intra-day and inter-day precision of the assay method were lower than 2%, and the accuracy was within the range of 95 - 105%. The determined percentages of LH and SAC in coamorphous solid were 74.12 ± 0.32 (%) and 25.98 ± 0.23 (%), respectively. Such results were very close to their corresponding theoretical percentages (74.28% and 25.72%, respectively), indicating the stoichiometry of coamorphous form was 1:1 for LH and SAC.

3.2. Formation of amorphous LH and coamorphous LH-SAC The XRPD of crystalline LH, SAC, physical mixture of crystalline LH and SAC at the mole ratio of 1:1, amorphous LH, SAC precipitate prepared by rotary vacuum evaporation and coamorphous LH-SAC are shown in Figure 2. Crystalline LH exhibited characteristic diffraction peaks at 11.56°, 14.04°, 15.24°, 15.64°, 16.60°, 17.24°, 19.64° and 22.04° 2θ (Figure 2a). In addition, overlapped diffraction peaks of LH and SAC (Figure 2b) were observed in their physical mixture (Figure 2c). The XRPD pattern of vacuum evaporation product of LH solution showed that the characteristic peaks of crystalline LH had completely disappeared and only a halo was observed, 11



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suggesting the formation of amorphous LH (Figure 2d). In addition, the absence of sharp diffraction peaks in XRPD was observed on the precipitate of LH and SAC mixed in the molar ratio of 1:1, suggesting the formation of a coamorphous LH-SAC solid after evaporation of methanol and subsequent solidification (Figure 2f). However, under the same preparation condition, SAC could not form amorphous state (Figure 2e). Other methods such as milling, quenching of melt and spray-drying also could not transfer the crystalline SAC to amorphous state (data not shown). Therefore, the precipitate of LH and SAC at the molar ratio of 1:1 was further proved to be a coamorphous system, instead of a physical mixture of amorphous LH and amorphous SAC.

3.3. Thermal behavior of amorphous and coamorphous systems DSC curves of crystalline LH, SAC, the 1:1 physical mixture of crystalline LH and SAC, amorphous LH and coamorphous LH-SAC are shown in Figure 3. Crystalline systems can be characterized by their melting points, whereas the characteristic kinetic parameter of an amorphous material is the glass transition temperature (Tg). The glass transition, recrystallization (Trc) and melting temperature (Tm) of the studied materials were measured and marked in Figure 3. The endothermic melting peak of crystalline LH split into two endotherms at 254.8-275.0 ºC (Figure 3Aa), which could be attributed to the thermal degradation of LH at the temperature close to 253 ºC

27

. SAC had a sharp fusion endotherm at 226.9 ºC (Figure 3Ab), which agreed

with its reported value.

28

The 1:1 physical mixture of LH and SAC showed only one melting 12


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endotherm at 171.27 ºC (Figure 3Ac) when the heating rate was set at 10 oC/min for DSC characterization. However, the physical mixture demonstrated two distinguishing endothermic peaks when decreasing the heating rate to 2 oC/min (Figure 3B), suggesting the single melting peak at 171.27 oC (10 oC/min) was not due to the formation of the single-phase eutectic mixture. Observation on the Melting Point Analyzer showed that LH could partially dissolve in the melt SAC solution and completely melt at around 245 oC, which further confirmed the above speculation. Such phenomenon was also observed for physical mixtures of repaglinide and SAC in various molar ratios. 15 Amorphous LH showed a glass transition event at 67.43 ºC and a sharp exothermic peak of crystallization at 174.94 ºC. The endothermic peak at 248.66 ºC was attributed to the degradation of the recrystallized LH (Figure 3Ad). On the other hand, only a single Tg value at 65.67 ºC was observed in the coamorphous LH-SAC mixture (Figure 3Ae), indicating the formation of a single-phase coamorphous system of LH and SAC (not the physical mixture of amorphous LH and amorphous SAC), which was consisting with the XRPD halo of the coamorphous sample (Figure 2f). A small exothermic peak at 152.83 ºC may be attributed to the recrystallization of coamorphous system. In comparison to the sharp recrystallization peak of amorphous LH, the recrystallization peak of coamorphous LH-SAC was much smaller (endothermic enthalpy: -31.88 vs -79.01 J·g-1), suggesting less degree of recrystallization of coamorphous LH-SAC. In order to recrystallize, the molecules have to break the molecular interaction within a coamorphous system and then rearrange to form the new interactions. Thus, in most cases the amorphous material with strong molecular interactions exhibited higher stability than those with weak ones. In addition to the steric effect in coamorphous LH-SAC 13



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system, formation of hydrogen bonds between LH and SAC molecules (shown in section 3.4) would further stabilize the amorphous state of LH and SAC by lowering the molecular mobility of the components. 4

3.4. Interaction between LH and SAC The IR spectra of studied samples (crystalline LH, lurasidone, SAC, physical mixture of crystalline LH and SAC (1:1 mole ratio), amorphous LH and coamorphous LH-SAC) are shown in Figure 4. LH showed typical vibrations of carbonyl group (C=O) at 1687.5 cm-1 and aliphatic C-H stretch at 2936 cm-1 (Figure 4a). In comparison to the IR spectrum of lurasidone base form (Figure 4b), LH exhibited another strong peak at 2258 cm-1, which was attributed to positive charged N+-H stretch. Such N+-H stretch formed FTIR peak was also observed on lidocaine hydrochloride

29

and meclizine hydrochloride.

30, 31

Stretching frequencies observed at 3092.9

cm-1 and 1719.0 cm-1 were attributed to N-H and C=O in the secondary amide group of SAC (Figure 4c), which was consistent with previous report.

28

The IR spectrum of physical mixture

was the superposition of crystalline LH and SAC (Figure 4d). Comparing with crystalline LH, the IR spectrum of amorphous LH showed peak shifts (2258.0 → 2441.5 cm-1 for N+-H group, 1687.5 → 1692.8 cm-1 for C=O group, and 2936.0 → 2931.9 cm-1 for C-H stretch) and reduction in peak intensities with peak broadening (especially N+-H stretch) (Figure 4e). Such changes in the peak position and shape after amorphization of LH may be due to disruption of the structured crystal lattice into the amorphous state with lack of long-range order and rearrangement of LH molecular conformations. 32 14


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In comparison to physical mixture of LH and SAC at the mole ratio of 1:1 (Figure 4d), the IR spectrum of coamorphous LH-SAC (1:1) showed distinguishing absorption peaks (Figure 4f). In coamorphous LH-SAC, the typical C=O stretching of SAC demonstrated a significant hypsochromic shift (1716.7 → 1734.1 cm-1); in addition, the absorption peak at 1693.0 cm-1 assigned to the C=O stretch of LH in the coamorphous LH-SAC was in accordance with the absorption peak at 1692.8 cm-1 of amorphous LH, indicating the C=O group in LH did not participate in the intermolecular interaction. However, the broadened N+-H stretching peak of LH in coamorphous LH-SAC showed a significant hypsochromic shift (2441.5 → 2633.6 cm-1) in comparison to that in amorphous LH. Therefore, the hypsochromic shifts in the C=O group of SAC and N+-H group of LH demonstrated the formation of charge assisted hydrogen bond between SAC and LH in the coamorphous LH-SAC mixture (Figure 5). Lobmann et al. found that two intermolecular hydrogen bonds, formed between the carboxylic groups of indomethacin and naproxen in coamorphous binary drug systems, resulted in the disruption of the dimers of each drug. It might be assumed that both components at the 1:1 molar ratio may be regarded as an interconnected state, forming a heterodimer, which can be regarded as an independent heterodimeric compound.

9, 33

In addition, the formed hydrogen bond could strengthen the

linkage between LH and SAC and prevent the conversion into crystalline state under both storage and dissolution conditions.

3.5. Solubility enhancement The pH-solubility profiles of crystalline LH, amorphous LH, physical mixture of crystalline LH 15



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and SAC (1:1 mole ratio), physical mixture of amorphous LH and SAC (1:1 mole ratio), and coamorphous LH-SAC in PBS (0.05 M, pH = 2~6.8) are depicted in Figure 6. It was shown that LH in both crystalline form and amorphous form demonstrated pH-dependent solubility profiles. In addition, LH achieved the maximum solubility at pH 3.8, which should be attributed to pHmax effect of organic hydrochlorides such as propranolol hydrochloride.

34, 35

Previous work on

pH-solubility profiles showed that it is possible to saturate simultaneously the unionized and ionized species at a particular pH called pHmax. When weak base is dissolved in an aqueous solution, equilibrium exists between the unionized species and ionized species, which can be described by Henderson–Hasselbalch equation 36 as follow: pH = pK a − log

Ci Cu

(Eq. 1)

Where Ci and Cu are the concentration of ionized species and unionized species, respectively. At a particular pH (pHmax), when both the ionized and unionized species can be simultaneously saturated, Eq. 1 can be expressed at the saturated state as: pH max = pK a − log

Si Su

(Eq. 2)

Where Si and Su are solubilities of ionized and unionized species, respectively. Si can be experimentally estimated at pH ≪ pHmax since the fraction of unionized species is very low at such pH. Conversely, Su can be experimental estimated at pH ≫ pHmax since the fraction of ionized species is very low at such pH. In the current study, Si and Su of crystalline LH were experimentally determined to be 0.22 mg·mL-1 and 2.4×10-6 mg·mL-1 at pH 2 and pH 6.8, respectively. pKa of lurasidone was predicted to be 8.5 by Chemaxon software (Version 6.2, 16


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ChemAxon Ltd.). According to Eq. 2, the calculated pHmax of LH was 3.5, which was close to the experimental pH value 3.8 (Figure 6). In comparison to crystalline LH, amorphous LH shared almost the same equilibrium solubility values in phosphate buffers with various pH values, which was due to solvent-mediated recrystallization. Since water has a relatively lower Tg (135 K) than that of common amorphous materials, the water-induced plasticization will lead to the transformation of amorphous materials towards their stable crystalline form. 37 The physical mixture of crystalline LH and SAC did not show any significant enhancement in solubility of crystalline LH in various pH buffers, thus SAC itself could not increase the solubility of crystalline LH significantly. However, the physical mixture of amorphous LH and SAC demonstrated a pH-dependent solubility profile over that of amorphous LH and significantly enhanced the solubilities of amorphous LH at various pH buffers, indicating SAC might play as a recrystallization inhibitor like PVP. 38 Once hydrophilic SAC quickly dissolves in aqueous medium, it may be absorbed onto the surface or into the interspace of amorphous LH materials, and subsequently inhibits the recrystallization of amorphous LH by providing physical barriers. In addition to significantly improving LH solubilities than amorphous and crystalline LH, coamorphous LH-SAC exhibited a distinct solubility profile with pH-independent property in the range of pH 2 to 5.5, which was advantageous over the physical mixture of amorphous LH and SAC without intermolecular interaction. This indicates that the formed hydrogen bond between LH and SAC in coamorphous LH-SAC probably plays a critical role for such phenomenon. 17



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Since the predicted pKa of lurasidone base form was 8.5, its salt form LH would release H+ in water and presented to be an acidic compound with pKa of 5.5. As the balanced chemical equation of organic hydrochloride (Eq. 3) 39, When pH < 5.5, LH mainly presents as protonated form and provides the ionic bond N+-H to form charge-assisted hydrogen bond with C=O of SAC, and subsequently coamorphous LH-SAC could be regarded as a single heterodimer instead of two individual amorphous components. Therefore, coamorphous LH-SAC exhibited pH-independent solubility profile in the range of pH 2 to 5.5; while pH > 5.5, LH would deprotonate to form lurasidone and lose the N+-H bond, and hence lose the hydrogen bond in coamorphous LH-SAC. The breakdown of hydrogen bond between LH and SAC would increase the molecular mobility of drug and thus the ability of amorphous drug to nucleate and recrystallize. In addition, the solubility decrease of LH itself at higher pH should also be considered.  → − N + H 3O + (Deprotonated) (Protonated) − NH + + H 2 O ← 

(Eq. 3)

When contacting aqueous medium, the embedded SAC between LH molecules in the coamorphous LH-SAC will exhibit several effects: (1) inhibiting recrystallization of LH by steric effect; (2) increasing the disordered state of amorphous LH in coamorphous LH-SAC in comparison to the pure amorphous LH; and (3) the formed hydrogen bond between LH and SAC might also facilitate the dissolution of LH resulting from the formation of heterodimer with addition of hydrophilic part with inner short-range order. 9 In comparison to crystalline or amorphous LH, such solubility enhancement and pH-independent property of coamorphous LH-SAC would result in improved in vivo dissolution 18


Page 19 of 38

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rate and decreased individual variation of LH dissolution in gastric juice with different pH (i.e. fast/fed condition and physiological difference) after oral administration, respectively. Consequently, the coamorphous LH-SAC may benefit the rapid dissolution and enhanced in vivo absorption of LH after oral administration.

3.6. Intrinsic dissolution profiles The intrinsic dissolution profiles of LH in coamorphous LH-SAC compared to crystalline and amorphous LH are shown in Figure 7. Crystalline LH exhibited a linear release profile with the intrinsic dissolution rate (IDR) of 0.0066 mg·cm-2·min-1. Amorphous LH underwent a rapid dissolution behavior in first 15 min with the IDR of 0.0575 mg·cm-2·min-1, followed by a slow dissolution after 15 min with the IDR of 0.0098 mg·cm-2·min-1. The initial rapid dissolution of amorphous LH could be attributed to its lack of long range molecular order and higher Gibbs free energy than crystalline LH

40, 41

, while the following significant reduction of IDR (20 min

after dissolution test) was due to its proclivity to undergo solvent-mediated recrystallization. The optical phenomenon of birefringence was observed on the surface of initially amorphous LH tablet (Figure S1 in Supporting Information) by polarizing microscope (Leica DMLP, Leica Microsystems Wetzlar GmbH, Wetzlar, Germany), which was the typical metastable issue associated with amorphous APIs.

5

Such phenomenon has also been reported on amorphous

indomethacin 42 and cimetidine 43. Different from amorphous LH, coamorphous LH-SAC showed a linear release profile with a single IDR of 0.0371 mg·cm-2·min-1. No birefringence was observed on the surface of 19



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coamorphous LH-SAC tablet, indicating the absence of recrystallization during dissolution period. In addition to steric effect of the inserted SAC, this is profited from the intermolecular interaction present in the binary system which is strong enough to prevent the disruption of hydrogen bonds between LH and SAC molecules during dissolution.

43

In comparison to

crystalline LH, coamorphous LH-SAC showed a 5.6-fold increase of IDR, which was primarily due to the lack of lattice energy brought about by long-range disorderliness of the coamorphous form. The increased dispersion of LH in amorphous state was also conducive to the rapid dissolution profile of coamorphous LH-SAC. 10

3.7. Concentration-time profile under supersaturated conditions The dissolution study under supersaturated conditions was performed to observe the spent time for LH to achieve supersaturated concentration prior to recrystallization, and to compare the metastable solubilities between amorphous LH and coamorphous LH-SAC in two dissolution media (0.2 M HCl and 0.2 M PBS 3.8). The supersaturated dissolution profiles of crystalline LH, amorphous LH and coamorphous LH-SAC in these two media are shown in Figure 8. As expected, water-insoluble crystalline LH had a very slow and low dissolution in both media. The concentration of LH in supersaturated suspension kept consistent with a straight line parallel to the abscissa after 0.5 h. Amorphous LH showed distinctive supersaturated dissolution profiles in both media. Its peak dissolution amount was attained rapidly before 1 h and then declined to approach the dissolution profile of crystalline LH. The notable dissolution decline is a result of precipitation of 20


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a more stable but much less soluble crystalline form, confirming the existence of supersaturation-mediated phase transformation. The precipitation or crystallization process involves three major steps including, the development of supersaturation, followed by nucleation and the subsequent growth.

44

As the thermodynamic driving force for nucleation and growth,

supersaturation may cause the reprecipitation of dissolved drug in dissolution medium once the concentration exceeds the equilibrium solubility.

45

Amorphous LH had a much extensive

reprecipitation at the early stage of supersaturated dissolution than amorphous repaglinide 46 and itraconazole

47

. The nucleation feature of an amorphous material can be described using the

homogeneous nucleation theory. 48

J = N 0 v exp[

− 16πv 2γ 3 ] 3(kT ) 3 (ln(S )) 2

(Eq. 4)

Where J is the number of nuclei formed per unit of time and volume, N0 is the number of molecules of the crystallizing phase in a unit volume, v is the frequency of molecular transport at the solid–liquid interface, and γ represents the interfacial energy per unit area between the medium and the nucleating cluster. S represents the degree of supersaturation, k is the Boltzman constant and T is the absolute temperature. According to this equation, the increased degree of supersaturation results in the increase of nucleation rate. Different from amorphous LH, coamorphous LH-SAC had no significant decrease in supersaturated dissolution over 24 h in both media, as shown in Figure 8, indicating the absence of recrystallization during the dissolution of this single-phase amorphous binary system. Although this coamorphous system had a lower dissolution at the early stage, it had an actual 21



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Page 22 of 38

solubility advantage over amorphous LH since it averts the proclivity of solvent-mediated recrystallization. This improvement is attributed to the involvement of the guest molecule SAC as discussed above. It can be inferred that the interaction between LH and SAC molecules inhibits the occurrence of nucleation and crystal growth. The prominent enhancement in supersaturation dissolution demonstrated the feasibility of coamorphous LH-SAC for enhancing in vivo absorption of water-insoluble LH. Compared to amorphous LH, coamorphous LH-SAC had higher metastable solubility and longer time length for LH to be remained at supersaturated concentration. Supersaturation is important in enhancing the drug delivery of a poorly water-soluble drug. In a supersaturated system, the concentration of drug in solution is close to or greater than its solubility, allowing more amount of free drug in solution state to be available for absorption. This might consequently be in favor of its oral bioavailability. 15

3.8. Solid stability Solid stability is a great concern for thermodynamically unstable amorphous system. Amorphous state has a higher free energy than the stable crystal state. In high energy states, amorphous materials will tend to crystallize over time and under stress (temperature, humidity, etc). The conversion to more stable physical states will subsequently lead to changes with respect to solubility and dissolution rate. The XRPD patterns of amorphous and coamorphous LH-SAC before and after storage at 25 ºC/60% RH are compared in Figure 9. After 2 days, nine characteristic diffraction peaks (11.4°, 22


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13.86°, 15.08°, 15.44°, 16.36°, 17.08°, 19.5°, 20.74° and 21.88° 2θ) of crystalline LH transformed from amorphous LH were detected (Figure 9A). The intensity of diffraction peaks increased sharply at 7th day. The current XRPD diffractogram was similar to that of crystalline LH, suggesting a nearly complete conversion towards stable crystalline form. This reflects the common downside of amorphous materials. It was well established that absorbed water by an amorphous solid could work as a plasticizer to lower Tg of the solid and increase molecular mobility, thus accelerating the rate and extent of transformation process.

37

The degree of

crystallinity also increases with higher temperature as a result of the increased relaxation enthalpy of an amorphous solid over time.

49

Even at a temperature below Tg, crystallization

occurs and it’s a rule of thumb to store amorphous samples 50 °C below Tg to minimize physical changes. 50 In contrast, no characteristic diffraction peak of crystalline LH was detected in coamorphous LH-SAC (Figure 9B). Considering the detection sensitivity of XRPD, polarized light microscopy was used to observe the possibility of small amount of crystals in samples stored for 60 days. No birefringence was observed (Figure S2 in Supporting Information), indicating the absence of phase transition and thus the prominently enhanced solid stability by coamorphous formation. The single phase amorphous binary system (coamorphous LH-SAC) displayed superior physical stability over amorphous LH on account of the interaction between LH and SAC molecules, which theoretically decreases the free energy difference between crystalline and amorphous solids. Consequently, more power is needed for the transformation of coamorphous system and the rate of nucleation is lowered. 23



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4. CONCLUSIONS Amorphous LH and coamorphous LH-SAC were prepared by solvent evaporation method and identified by XRPD and DSC. In comparison to amorphous LH, coamorphous LH-SAC gained a significant increase in solubility, dissolution and physical stability. In addition, coamorphous LH-SAC exhibited a pH-independent solubility behavior, which was attributed to the formed charge-assisted hydrogen bonding interaction between the N+-H group of LH and the C=O group of SAC in coamorphous LH-SAC system. In conclusion, this study showed that coamorphous drug-excipient binary system is a promising strategy to improve the dissolution behavior and stabilize the amorphous state of poorly soluble drugs.

ACKNOWLEDGEMENTS This research was supported by The National Natural Science Fund (NO. 81202988), Natural Science Foundation of Jiangsu Province (BK20141351, BK20130659), the Fundamental Research Funds for the Central Universities (ZJ15027), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Qing Lan Project of Jiangsu Province.

24


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Supporting Information More photomicrographs by polarizing microscope are provided in the Supporting Information. This information is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author * Tel: +86 25 83379418; fax: +86 25 83379418; email: [email protected]

Author Contributions #

S. Qian and W. Heng contributed equally to this work.

Notes The authors declare no competing financial interest.

25



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Page 28 of 38

Table of Contents Graphic and Synopsis Figure 1. Molecular structure of lurasidone hydrochloride (LH) (a) and saccharin (SAC) (b) Figure 2. PXRD patterns for crystalline LH (a), SAC (b), 1:1 physical mixture of LH and SAC (c), amorphous LH, (d) SAC prepared by the same method as amorphous LH (e), and coamorphous LH-SAC (1:1) (f)

Figure 3. (A): DSC thermograms for crystalline LH (a), SAC (b), 1:1 physical mixture of LH and SAC (c), amorphous LH (d) and coamorphous LH-SAC (e) determined at 10 o

C/min, (B): DSC thermograms for 1:1 physical mixture of LH and SAC determined

at 2 oC/min

Figure 4. FTIR spectra for crystalline LH (a), lurasidone (b), SAC (c), 1:1 physical mixture of LH and SAC (d), amorphous LH (e) and coamorphous LH-SAC (f)

Figure 5. Schematic packing motif of coamorphous LH-SAC. The dash line between N+-H of LH and C=O of SAC indicated the assumed H-bonding in the coamorphous 1:1 molar mixture.

Figure 6. Equilibrium solubility of crystalline LH, amorphous LH, physical mixture of crystalline LH and SAC (1:1), physical mixture of amorphous LH and SAC (1:1) and coamorphous LH-SAC in phosphate buffers (n = 3). *: p < 0.05, vs crystalline LH; #:

p < 0.05, vs amorphous LH

Figure 7. Intrinsic dissolution profiles of crystalline LH, amorphous LH and coamorphous LH-SAC in 0.2 M PBS 3.8 (n = 6)

Figure 8. Supersaturated dissolution profiles of crystalline LH, amorphous LH and coamorphous LH-SAC in 0.2 M HCl (A) and 0.2 M PBS 3.8 (B) (n = 6).

Figure 9. PXRD patterns for amorphous LH (A) and coamorphous LH-SAC (B) stored at 25 ºC /60% RH over specified period

28


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Figure 1.

(a) H H

O N N

H

H

Cl

N

S

N

H H H

O

O

(b) NH S O O

29



Figure 2. (f)

(e)

(d) Intensity

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 30 of 38

(c)

(b)

(a) 10

20

30

40

2θ (°)

30


Page 31 of 38

Figure 3.

A

(e) o

Tg: 65.67 C o

T: 248.66 C

o

Trc: 152.83 C Enlarge

Heat flow endo up

∆H: -31.88 J.g

-1

(d)

o

Trc: 174.94 C -1

∆H: -79.01 J.g

Enlarge o

Tg: 67.43 C

(c)

o

Tm: 171.27 C

o

Tm: 226.9 C

(b)

o

T: 254.8 C

100

200

(a)

300

o

Temperature( C)

B

Heat flow endo up

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


160

180

200

220

240

260

280

300

o

Temperature ( C)

31



Figure 4.

(f)

6.4

1734.1 2936.9 2633.5

5.6

1693.0

(e)

4.8

2931.9

Transmittance (%)

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 32 of 38

2441.5 1692.8

(d)

4.0

3092.9 3.2

1716.7

2936.3

2258.2

2.4

1687.3

(c)

1719.2

3092.9

(b)

1.6

2918.8

0.8

0.0

4000

1699.8

2936.0 3500

3000

2258.0 2500

(a)

1687.5

2000

1500

1000

500

-1

Wavenumber (cm )

32


Page 33 of 38

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Figure 5.

33



Figure 6. crystalline LH amorphous LH coamorphous LH-SAC physical mixture (crystalline LH+SAC) physical mixture (amorphous LH + SAC)

1.5

#

1.2

-1

Solubility (mg⋅ml )

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 34 of 38

0.9

*#

#

#

*#

*#

*#

*#

*#

# 0.6

0.3

#

*# 0.0 2

3

4

5

6

pH

34


Page 35 of 38

Figure 7.

3.5

Crystalline LH 2 y=0.0066x + 0.207 (r = 0.9968) 3.0

Amorphous LH 2 y=0.0575x - 0.0762 (5-15 min, r = 0.9942) 2 y=0.0098x + 0.7082 (15-90 min, r = 0.9778)

2.5 -2

Amount released (mg⋅cm )

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


Coamorphous LH-SAC 2 y=0.0371x+0.0133 (r =0.9934)

2.0

1.5

1.0

0.5

0.0 20

40

60

80

100

Time (min)

35



Figure 8.

-1

LH concentration (mg⋅mL )

1.5

A

Crystalline LH Amorphous LH Coamorphous LH-SAC (1:1)

1.2

0.9

0.6

0

5

10

15

20

25

Time (h)

1.5

Crystalline LH Amorphous LH Coamorphous LH-SAC

B

1.2 -1

LH concentration (mg⋅mL )

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 36 of 38

0.9

0.6

0.3

0.0 0

5

10

15

20

25

Time (h)

36


Page 37 of 38

Figure 9. 25000

B

Coamorphous LH-SAC 60 days

20000

fresh prepared 15000

Intensity

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 Amorphous LH

10000

7 days 5000

2 days 0

fresh prepared 10

20

30

40

2θ (°)

37



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Page 38 of 38

For Table of Contents Use Only

Coamorphous Lurasidone Hydrochloride−Saccharin with Charge-assisted Hydrogen Bonding Interaction Shows Improved Physical Stability and Enhanced Dissolution with pH-independent Solubility Behavior Shuai Qian #,†, Weili Heng #,†, Yuanfeng Wei †, Jianjun Zhang *,‡, Yuan Gao †

TOC graphic

TOC synopsis In comparison to amorphous lurasidone hydrochloride (LH), coamorphization of LH with saccharin (SAC) demonstrates superior physical stability, enhanced dissolution rate and improved solubility with pH-independent solubility behavior in pH range of 2 to 5.5. The coamorphization effect and charge-assisted hydrogen bond in coamorphous LH-SAC were speculated to be responsible for the above phenomena by prohibiting the recrystallization of LH. 38


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