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Solution-mediated phase transformation at particle surface during cocrystal dissolution
Journal of Drug Delivery Science and Technology 56 (2020) 101566
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Solution-mediated phase transformation at particle surface during cocrystal dissolution
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Maaya Omori, Taiga Uekusa, Jumpei Oki, Daisuke Inoue, Kiyohiko Sugano∗ Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga, 525-8577, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Cocrystal Carbamazepine Supersaturation Non-sink Dissolution test Induction time Mean diffusion time
In this study, we investigated solution-mediated phase transformation (SMPT) during cocrystal particle dissolution. When the solubility of a cocrystal is higher than that of the free form, the concentration of the free form can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Therefore, SMPT may occur either in the bulk phase or at the particle surface (PS-SMPT). Carbamazepine - glutaric acid cocrystal (CBZGLA) was used as a model cocrystal. Dissolution tests were performed under a non-sink condition. The residual particles were analyzed by polarized light microscopy (PLM), scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. Solvent-shift bulk phase precipitation tests and real-time PLM observation of PS-SMPT were also performed. In the dissolution test, little or no supersaturation was observed. CBZ-GLA particles rapidly and completely transformed to aggregates of CBZ dihydrate (CBZ DH) (> 95% within 3 min). The outer shape of the aggregates preserved that of initial CBZ-GLA particles, but distinctly differed from CBZ DH precipitated from the bulk phase. Real-time PLM observation revealed that PS-SMPT started within several seconds after contact with the medium. These results suggested that CBZ-GLA particles transformed to the aggregates of CBZ DH via PS-SMPT.
1. Introduction
formation may induce crystal lattice disorder to promote crystallization of a free form [11]. Furthermore, supersaturation characteristics cannot be evaluated under a sink condition. Non-sink dissolution tests have been used to assess the dissolution of cocrystal particles and the subsequent supersaturation and precipitation of the free form drug [6,12]. It has often been implicitly assumed that the free form precipitates from the supersaturated bulk phase after the dissolution of cocrystal particles. However, during the dissolution process, drug molecules diffuse through the unstirred water layer (UWL) adjacent to the particle to reach the bulk phase, depending on the concentration gradient around the particle. When a cocrystal shows a higher solubility than its free form, the free drug concentration can be markedly supersaturated at the dissolving cocrystal surface, leading to SMPT at the particle surface. Therefore, in a non-sink dissolution test of cocrystal particles, SMPT may occur either in the bulk phase or at the particle surface (BP-SMPT and PS-SMPT, respectively). A good understanding of SMPT during particle dissolution is required to develop an appropriate cocrystal formulation. However, in most literature, BPSMPT and PS-SMPT have been discussed ambiguously [13,14]. So far, based on limited experimental data, only a few reports speculated that cocrystal particles transformed to a free form via PS-SMPT during cocrystal particle dissolution [6,13,15]. To the best of our knowledge,
Recent drug candidates tend to be poorly soluble in aqueous media [1,2]. These drug candidates often show incomplete, variable, and less than dose proportional oral absorption. To increase the concentration of drug molecules dissolved in the gastrointestinal fluid, a poorly soluble drug candidate is often converted to a supersaturable active pharmaceutical ingredient (sAPI), such as cocrystals, salts, metastable crystal forms, and amorphous solid forms [3,4]. Cocrystal formation can transiently increase the concentration of a drug by orders of magnitude [5]. However, this transiently high concentration presents a risk for solution-mediated phase transformation (SMPT) to a free form during the dissolution process [6]. Previously, the dissolution mechanism of cocrystals has been mainly investigated using intrinsic dissolution tests (rotating disk or static disk method) under a sink condition. Several reports showed that the surface of a cocrystal disk converted to a free form via SMPT [7–9]. However, it is not clear whether SMPT observed on the disk surface also takes place at the particle level. The size of a disk (> 1 mm) is significantly greater than that of drug particles (usually < 0.1 mm). Hydrodynamics around a disk could be significantly different from that around a suspended particle [10]. High compression pressure applied during disk ∗
Corresponding author. E-mail address: [email protected] (K. Sugano).
https://doi.org/10.1016/j.jddst.2020.101566 Received 9 January 2020; Received in revised form 31 January 2020; Accepted 31 January 2020 Available online 06 February 2020 1773-2247/ © 2020 Elsevier B.V. All rights reserved.
Journal of Drug Delivery Science and Technology 56 (2020) 101566
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the small intestine [20]. The dose/fluid volume ratio was set to reflect the clinical dose (200 mg) and the intestinal fluid volume (50–250 mL) [21,22]. The paddle rotation speed was set to 100 rpm. Dissolution samples (0.40 mL) were withdrawn, filtered, and diluted by ethanol at specified time intervals (15, 30, 60, 120, 240, 360, and 1440 min). CBZ concentration was determined as described above. Dissolution tests were performed in triplicate. In a separate dissolution test, residual particles were collected at 1, 3, 10 and 30 min by vacuum filtration and analyzed by polarized light microscope (PLM, Olympus CX-43, Olympus Corporation, Tokyo, Japan), scanning electron microscope (SEM, TM-1000, Hitachi HighTechnologies Corporation, Tokyo, Japan), PXRD, and DSC.
detailed experimental evidences supporting PS-SMPT of cocrystals have not been reported. The purpose of the present study was to investigate SMPT of cocrystal particles during dissolution. Carbamazepine - glutaric acid cocrystal (CBZ-GLA) was used as a model drug. Previously, the surface of a CBZ-GLA disk was reported to convert to CBZ dihydrate (CBZ DH, thermodynamically most stable in aqueous media) during the rotating disk dissolution test [9]. In the present study, detailed analyses of the residual particles in non-sink dissolution tests were performed. In addition, solvent shift precipitation tests were performed to differentiate BP-SMPT from PS-SMPT. Furthermore, we directly observed SMPT of CBZ-GLA particles using a novel microscopic technique we recently developed [16,17].
2.2.5. Solvent-shift precipitation test Solvent-shift precipitation tests were performed using the same apparatus, dissolution medium, and paddle rotation speed with the non-sink dissolution test [23]. A concentrated dimethylacetamide solution of CBZ AH (0.5 mL) was added to blank FaSSIF at 37 °C. The initial bulk phase concentration was set to 2.1–2.4 mM. Samples were withdrawn, filtered, and diluted by ethanol at specified time intervals (0, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 1440 min). CBZ concentration was determined as described above. Solvent-shift precipitation tests were performed in triplicate.
2. Materials and methods 2.1. Materials Carbamazepine (anhydrous, form III) (CBZ AH), glutaric acid (GLA), NaH2PO4 2H2O, NaCl, 8 N NaOH, and ethanol were purchased from Wako Pure Chemical Industries, Ltd (Osaka, Japan). 2.2. Methods 2.2.1. Preparation of carbamazepine dihydrate and glutaric acid cocrystal CBZ DH was prepared by suspending CBZ AH in distilled water with vigorous stirring for 30 h. The resulting crystals were harvested by vacuum filtration. CBZ-GLA 1:1 cocrystal was prepared as previously reported [18]. CBZ AH (14.2 g) and GLA (4.0 g) were added to acetonitrile (150 mL) in a glass beaker and warmed at 60 °C. The solution was then stored at room temperature (25 ± 2 °C) for 7 days. The CBZ-GLA particles were harvested by vacuum filtration. The average size of CBZ-GLA particles was about 27 μm (determined by microscopic image analysis using ImageJ) [19]. The solid forms of CBZ DH and CBZ-GLA were confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) (see the PXRD and DCS sections).
2.2.6. Real-time polarized light microscope observation of PS-SMPT The experimental procedures of real-time PLM observation have been previously reported in detail [16]. In brief, CBZ-GLA particles (0.2–0.4 mg) were placed on a slide glass and covered with another slide glass. These two slide glasses were tightly pinched by using two binder clips to immobilize the particles between the slide glasses. The sample temperature was maintained at 37 °C by a glass plate heater (BLAST Inc., Kanagawa, Japan). Blank FaSSIF (30 μL) was penetrated between the slide glasses by capillary action from the side of the slide glass using a micropipette under a polarized light microscope. 3. Results 3.1. Dissolution profiles of carbamazepine – glutaric acid cocrystal (CBZGLA) and carbamazepine dihydrate (CBZ DH) under non-sink condition
2.2.2. Powder X-ray diffraction Samples were ground with a mortar and pestle prior to PXRD analysis. A sample was placed on a zero-diffraction plate and analyzed by PXRD (Rigaku Ultima IV, Rigaku corporation, Tokyo, Japan). Data was collected from 5 to 35° (2θ) at a step size of 0.02° and scanning speed of 10 deg/min with Cu Kα radiation generated at 40 mA and 40 kV. For the quantification of CBZ-GLA and CBZ DH in the dissolution test, a standard curve was prepared using the physical mixtures of CBZ-GLA and CBZ DH (0, 5, 20, 40, 80 and 100% of CBZ-GLA, r2 = 0.95). The percentage of CBZ-GLA was calculated from the peaks at 12.3° and 13.6° for CBZ DH and CBZ-GLA, respectively.
The time course profiles of CBZ concentration dissolved in the bulk phase (CCBZ, bulk) are shown in Fig. 1. The amount of CBZ added to the medium was 50 mg in 50 mL (as of CBZ free form, molecular
2.2.3. Differential scanning calorimetry The sample was placed in an aluminum pan (non-sealed) and analyzed by DSC at 10 °C/min under nitrogen gas (DSC60 plus, Shimazu Corporation Kyoto, Japan). The residual percentage of CBZ-GLA was calculated from the enthalpy of melting at 126 °C. A standard curve was prepared using the physical mixtures of CBZ-GLA and CBZ DH (0, 5, 20, 40, 80 and 100% of CBZ-GLA, r2 = 0.94). 2.2.4. Non-sink dissolution test The dissolution, supersaturation, and precipitation profiles of CBZGLA and CBZ DH were evaluated by a mini-paddle dissolution test under a non-sink condition (NTR-6200AC, Toyama Sangyo Co., Ltd., Osaka, Japan). CBZ particles (0.21 mmol, equivalent to 50 mg CBZ AH) were added to the fasted state simulated intestinal fluid without bile micelle (blank FaSSIF, 29 mM phosphate, 105 mM NaCl, pH 6.5, 50 mL) at 37 °C [20]. pH 6.5 was chosen because it is the representative pH of
Fig. 1. Dissolution profiles of CBZ-GLA and CBZ DH in blank FaSSIF for 0–4 h (mean ± S.D., n = 3). CBZ concentration reached a plateau after 4–6 h for both CBZ-GLA and CBZ DH (data not shown). 2
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Fig. 2. PXRD patterns of initial and residual particles in the non-sink dissolution test. Fig. 4. PLM and SEM images of initial and residual particles after 10 min in the non-sink dissolution test. (A) PLM, (B) SEM.
weight = 236). Therefore, the theoretical maximum CCBZ, bulk was 4.2 mM. Due to rapid dissolution, it was difficult to compare the initial dissolution rates. In the case of CBZ DH, CCBZ, bulk reached a plateau at 0.90 ± 0.02 mM after 4–6 h. This value is similar to the equilibrium solubility of CBZ DH at 37 °C reported in the literature [11,24]. In the case of CBZ-GLA, CCBZ, bulk showed little or no supersaturation, reaching a plateau at 0.93 ± 0.02 mM after 4–6 h. The residual particles were analyzed by powder X-ray diffraction (PXRD) (Fig. 2), differential scanning calorimetry (DSC) (Fig. 3), polarized light microscopy (PLM) (Fig. 4A), and scanning electron microscopy (SEM) (Fig. 4B). The residual particles were collected from the dissolution medium at each time point and immediately separated from the fluid to avoid solid form transformation before analysis. The residual percentage of CBZ-GLA was quantified by PXRD and DCS using the standard curves from the physical mixtures of CBZ-GLA and CBZ DH (r2 > 0.94) (Fig. 5). When using PXRD for quantification, the diffraction pattern may only reflect the residual percentage of CBZGLA at the particle surface. In addition, the effect of preferred orientation may interfere quantification, even when a sample is well ground before analysis. Therefore, the residual percentage of CBZ-GLA was quantified by both PXRD and DSC. CBZ-GLA rapidly and almost completely transformed to CBZ DH during the dissolution test (> 95% within 3 min). PLM and SEM images suggested that CBZ-GLA particles transformed to aggregates of needle-like crystals of CBZ DH while retaining the outer shape of the initial particle (Fig. 5).
Fig. 5. Residual percentage of CBZ-GLA in the non-sink dissolution test measured by DSC and PXRD.
3.2. Precipitation from the bulk phase The precipitation profiles of CBZ DH in the solvent-shift precipitation tests are shown in Fig. 6. After the addition of concentrated CBZ, the bulk phase became a homogeneous transparent solution, followed by precipitation of CBZ-DH. The critical supersaturation concentration for CBZ DH crystallization in the bulk phase was above 2.1 mM for the time scale of several hours (Fig. 6A). The induction time (tind) was calculated as the intercept of the precipitation line and the initial CCBZ, bulk value (CCBZ, bulk, ini). Fig. 6B shows the relationship between the induction time (tind) and the initial supersaturation ratio (S = CCBZ, bulk, ini/SCBZ DH (SCBZ DH: the equilibrium solubility of CBZ DH (0.90 mM))) (Supplemental information, Table S1). A linear correlation was observed between (log S)−2 and tind [25]. The precipitated CBZ DH particles were needle-like crystals with smooth surfaces without aggregation (Fig. 7) (the solid form was confirmed by PXRD and DSC (Supplemental information, Fig. S1).
3.3. Real-time solution-mediated phase separation observed under polarized light microscope (PLM) Fig. 3. DSC patterns of initial and residual particles in the non-sink dissolution test.
The real-time PLM images of CBZ-GLA after contact with blank 3
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Fig. 6. Results of bulk phase solvent-shift precipitation test. (A) Concentration time profiles (mean ± S.D., n = 3), (B) relationship between the initial supersaturation ratio (S) and the induction time (tind). The insert in (A) is the enlarged figure from 0 to 4 h.
to CBZ DH (> 95% within 3 min) (Figs. 2–4). Therefore, there is little or no CBZ-GLA dissolution after 3 min. The results of the solvent-shift precipitation tests showed that, once CBZ was dissolved in the bulk phase, CCBZ, bulk would maintain supersaturated concentration without precipitation for several hours up to 2.1 mM (Fig. 6A). Therefore, there was a concentration window (from 0.9 to 2.1 mM), which was sufficient to observe supersaturation in the bulk phase. In addition, the residual particles in the non-sink dissolution test were aggregates of CBZ DH crystals that preserved the outer shape of the initial CBZ-GLA particles (Fig. 4), but were distinctly different from CBZ DH precipitated from the bulk phase (Fig. 7). Therefore, it is unlikely that CBZ DH precipitated from the bulk phase. Rather, preservation of the outer shape of the initial particles suggests that CBZ-GLA particles transformed to CBZ DH via PS-SMPT. Furthermore, the real-time PLM observation suggested that SMPT occurred at the particle surface within several seconds after contacted with the medium (Fig. 8A). These experimental results provided further evidence to support PS-SMPT. In-line (in situ) solid form analysis, such as in situ Raman spectroscopy, may provide more direct evidence of PS-SMPT. This method has been used to observe SMPT at the fixed disk surface [8]. However, it is difficult to apply this method to rapid SMPT of suspended particles in an agitated medium. Instead of in-line analysis of suspended particles, we observed PS-SMPT in real-time under a polarized light microscope. Theoretically, when the precipitation induction time is shorter than the time scale of a process, free form precipitation takes place during that process. The time scale of diffusion across UWL adjacent to a particle (tdiff,UWL) can be approximately calculated as,
FaSSIF are shown in Fig. 8A. The surface texture of the CBZ-GLA particles started to change within several seconds after contact with blank FaSSIF. The appearance of the particles was similar to that recovered from the non-sink dissolution test. 4. Discussion As mentioned in the introduction, during the dissolution of cocrystal particles, solution-mediated phase separation (SMPT) may occur either in the bulk phase (BP-SMPT) or at the particle surface (PS-SMPT). It has often been implicitly assumed that the free form precipitates from the supersaturated bulk phase after the dissolution of cocrystal particles. However, since the concentration of the free form can be markedly supersaturated at the dissolving cocrystal surface, rapid precipitation of the free form can also occur at the cocrystal surface [29]. Therefore, in a non-sink dissolution test of cocrystal particles, it is anticipated that transient supersaturation would be observed in the bulk phase in the case of BP-SMPT, but not in the case of PS-SMPT. In the non-sink dissolution test of CBZ-GLA particles, little or no supersaturation was observed in the bulk phase (Fig. 1), suggesting that CBZ-GLA particles transformed to CBZ DH via PS-SMPT [6,13,15]. However, this result is not sufficient to firmly support PS-SMPT due to the following reasons: (I) the concentration - time profile observed in the bulk phase may be superficially caused by the balance of the dissolution of CBZ-GLA and the precipitation of CBZ DH, (II) the critical supersaturation ratio may be close to 1, and there may be no concentration window to observe supersaturation in the bulk phase (III), BP-SMPT may occur before the first sampling time point, and (IV) the solid form of the particles was identified off-line, so that solid form transformation might have been occurred before analysis. In this study, CBZ-GLA rapidly and almost completely transformed
tdiff , UWL ≈
h2 2D
(1)
where D is the diffusion co efficient, and h is the thickness of the UWL.
Fig. 7. PLM and SEM images of CBZ DH particles recovered from the bulk phase solvent-shift precipitation test. (A) PLM, (B) SEM. 4
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Fig. 8. CBZ-GLA to CBZ DH transformation. (A) Real-time PLM images of CBZ-GLA after contact with blank FaSSIF, (B) sectional schematic illustration of PS-SMPT for CBZ-GLA.
passive film of the free acid was formed on the particle surface in the early stage of dissolution to suppress the dissolution of the salt [17]. PSSMPT was also observed for pioglitazone HCl and tosufloxacin mesylate [31,32]. Thus, PS-SMPT can commonly occur among salts and cocrystals. PS-SMPT of other sAPIs, such as amorphous and metastable crystal forms, is under investigation. To induce supersaturation in the bulk phase, it is important to fine tune the solubility of a cocrystal to avoid PS-SMPT [15]. In addition, drug formulations need to be optimized to effectively utilize the solubilization potential of a cocrystal. Previously, Shiraki et al. reported that particle size reduction was effective in inducing a supersaturated drug concentration from a cocrystal [12]. Particle size reduction can reduce tdiff,UWL so that to increase the amount of drug molecules reaching the bulk phase. The addition of a polymer or a surfactant would be also effective [6,7,33–38]. The effects of cocrystal solubility, particle size, and precipitation inhibitors on PS-SMPT is under investigation. In conclusion, this study provided more conclusive evidence supporting PS-SMPT during cocrystal dissolution. Detailed PLM and SEM observations of residual particles in a dissolution test and real-time microscopic observation are useful to investigate PS-SMPT. Solventshift precipitation tests provide the characteristics of BP-SMPT. A good understanding of PS-SMPT during particle dissolution is of great importance in developing cocrystals.
In the case of small particles (particle radius (rp) < 30 μm), h can be approximated as h = rp [26,27]. The average radius of the CBZ-GLA particles was 14 μm. The diffusion coefficient of CBZ was estimated from the molecular weight to be 8.3 × 10−6 cm2/s [28]. From these data and Eq. (1), the tdiff,UWL value was estimated to be 110 ms. The mean induction time in the UWL (tind,UWL) should be smaller than this value for PS-SMPT. The tind,UWL value can be roughly calculated from the solubility of the cocrystal and the tind – log S relationship (Fig. 6B). Based on the solubility of CBZ-GLA cocrystal (54 mM) [5], the tind,UWL value was estimated to be 1.6 ms. Although extrapolating the tind value at 54 mM from the data in the range of 2.1–2.4 mM might be inaccurate, the estimated tind,UWL value was 2 orders of magnitude shorter than the tdiff,UWL value and thus did not negate PS-SMPT at least. The results of the present study were in good agreement with the previous result showing that the surface of a CBZ-GLA disk was transformed to CBZ-DH during an intrinsic dissolution test [29]. However, the CBZ-GLA disk was not completely transformed to CBZ DH after 10 min (based on PXRD analysis). In contrast, in the present study, CBZGLA particles were almost completely transformed to CBZ DH within 3 min. Therefore, the rate of SMPT at the particle surface might be faster than that at the disk surface. PS-SMPT proceeded inside the particle, probably because there were pores between the precipitated CDZ DH crystals on the surface (Fig. 8B). Yamashita et al. suggested that CBZ-GLA can be a self-template to enhance CBZ DH crystallization on the surface of CBZ-GLA [30]. This effect may also have accelerated PS-SMPT of CBZ-GLA particles. Recently, Huang et al. investigated the dissolution, supersaturation, and precipitation profiles of the indomethacin – saccharin cocrystal under a non-sink condition [6]. Microscopic observation of residual particles suggested that indomethacin free acid crystallized on the cocrystal surface during the dissolution process of cocrystals. However, supersaturation was observed in the bulk phase and precipitation occurred slowly (> 1 h). Yoshimura et al. have also suggested PS-SMPT of cocrystals, but solely based on the dissolution profile [15]. Therefore, it was not clear whether precipitation occurred via either PS-SMPT or BPSMPT in these studies. In the present study, together with the PXRD and DSC analyses of residual particles, the SEM and PLM observations provided further evidences supporting PS-SMPT. The result of the solvent-shift precipitation test suggested that BP-SMPT was highly unlikely. The result of the real-time PS-SMPT observation also supported PS-SMPT. Recently, we reported that PS-SMPT also occurred for drug salts. In the case of diclofenac sodium, in an acidic medium (pH < < pKa), a
CRediT authorship contribution statement Maaya Omori: Data curation, Validation, Writing - review & editing. Taiga Uekusa: Data curation. Jumpei Oki: Data curation. Daisuke Inoue: Supervision, Validation. Kiyohiko Sugano: Supervision, Funding acquisition, Writing - original draft. Declaration of competing interest The Author(s) declare(s) that they have no conflicts of interest to disclose. Acknowledgement This research was partly supported by AMED under Grant Number JP17ak0101074. Part of this study was presented at APSTJ annual meeting in Toyama, Japan (May, 2019). 5
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Appendix A. Supplementary data
carbamazepine, CrystEngComm 10 (2008) 856–864. [19] C.A. Schneider, W.S. Rasband, K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis, Nat. Methods 9 (2012) 671. [20] E. Galia, E. Nicolaides, D. Hörter, R. Löbenberg, C. Reppas, J.B. Dressman, Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs, Pharm. Res. (N. Y.) 15 (1998) 698–705. [21] C. Schiller, C.P. Fröhlich, T. Giessmann, W. Siegmund, H. Mönnikes, N. Hosten, W. Weitschies, Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging, Aliment. Pharmacol. Ther. 22 (2005) 971–979, https://doi.org/10.1111/j.1365-2036.2005.02683.x. [22] M. Grimm, M. Koziolek, M. Saleh, F. Schneider, G. Garbacz, J.P. Kühn, W. Weitschies, Gastric emptying and small bowel water content after administration of grapefruit juice compared to water and isocaloric solutions of glucose and fructose: a four-way crossover MRI pilot study in healthy subjects, Mol. Pharm. 15 (2018) 548–559, https://doi.org/10.1021/acs.molpharmaceut.7b00919. [23] S. Ozaki, Population balance model for simulation of the supersaturation–precipitation behavior of drugs in supersaturable solid forms, J. Pharm. Sci. 108 (2019) 260–267, https://doi.org/10.1016/j.xphs.2018.07.027. [24] Y. Kobayashi, S. Ito, S. Itai, K. Yamamoto, Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate, Int. J. Pharm. 193 (2000) 137–146. [25] S. Ozaki, T. Minamisono, T. Yamashita, T. Kato, I. Kushida, Supersaturation–nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms, J. Pharm. Sci. 101 (2012) 214–222. [26] R.J. Hintz, K.C. Johnson, The effect of particle size distribution on dissolution rate and oral absorption, Int. J. Pharm. 51 (1989) 9–17. [27] K. Sugano, Theoretical comparison of hydrodynamic diffusion layer models used for dissolution simulation in drug discovery and development, Int. J. Pharm. 363 (2008), https://doi.org/10.1016/j.ijpharm.2008.07.002. [28] A. Avdeef, Leakiness and size exclusion of paracellular channels in cultured epithelial cell monolayers-interlaboratory comparison, Pharm. Res. (N. Y.) 27 (2010) 480–489, https://doi.org/10.1007/s11095-009-0036-7. [29] H. Yamashita, C.C. Sun, Improving dissolution rate of carbamazepine-glutaric acid cocrystal through solubilization by excess coformer, Pharm. Res. (N. Y.) 35 (2018), https://doi.org/10.1007/s11095-017-2309-x. [30] H. Yamashita, C.C. Sun, Self-templating accelerates precipitation of carbamazepine dihydrate during the dissolution of a soluble carbamazepine cocrystal, CrystEngComm 19 (2017) 1156–1159, https://doi.org/10.1039/c6ce02418a. [31] T. Uekusa, K. Sugano, Effect of buffer capacity on dissolution and supersaturation profiles of poorly soluble drug salt, APSJT Annu. Meet, 2019, p. 236. Toyama. [32] Y. Tanaka, K. Sugano, Effect of buffer capacity on supersaturation profiles of tosufloxacin tosilate, APSTJ Annu. Meet, 2019, p. 263. Toyama. [33] M. Li, S. Qiu, Y. Lu, K. Wang, X. Lai, M. Rehan, Investigation of the effect of hydroxypropyl methylcellulose on the phase transformation and release profiles of carbamazepine-nicotinamide cocrystal, Pharm. Res. (N. Y.) 31 (2014) 2312–2325, https://doi.org/10.1007/s11095-014-1326-2. [34] M. Guo, K. Wang, N. Hamill, K. Lorimer, M. Li, Investigating the influence of polymers on supersaturated flufenamic acid cocrystal solutions, Mol. Pharm. 13 (2016) 3292–3307, https://doi.org/10.1021/acs.molpharmaceut.6b00612. [35] C. Wang, Q. Tong, X. Hou, S. Hu, J. Fang, C.C. Sun, Enhancing bioavailability of dihydromyricetin through inhibiting precipitation of soluble cocrystals by a crystallization inhibitor, Cryst. Growth Des. 16 (2016) 5030–5039, https://doi.org/10. 1021/acs.cgd.6b00591. [36] A. Alhalaweh, H.R.H. Ali, S.P. Velaga, Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media, Cryst. Growth Des. 14 (2014) 643–648, https://doi.org/10.1021/cg4015256. [37] M. Ullah, I. Hussain, C.C. Sun, The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance, Drug Dev. Ind. Pharm. 42 (2016) 969–976, https://doi.org/10.3109/03639045.2015. 1096281. [38] S. Qiu, J. Lai, M. Guo, K. Wang, X. Lai, U. Desai, N. Juma, M. Li, Role of polymers in solution and tablet-based carbamazepine cocrystal formulations, CrystEngComm 18 (2016) 2664–2678, https://doi.org/10.1039/c6ce00263c.
Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jddst.2020.101566. References [1] K. Sugano, A. Okazaki, S. Sugimoto, S. Tavornvipas, A. Omura, T. Mano, Solubility and dissolution profile assessment in drug discovery, Drug Metabol. Pharmacokinet. 22 (2007), https://doi.org/10.2133/dmpk.22.225. [2] A.M. Thayer, C. Houston, Finding solutions. Custom manufacturers take on drug solubility issues to help pharmaceutical firms move products through development, Chem. Eng. News 88 (2010) 13–18, https://doi.org/10.1016/j.jenvp.2009.05.001. [3] A.T.M. Serajuddin, Salt formation to improve drug solubility, Adv. Drug Deliv. Rev. 59 (2007) 603–616, https://doi.org/10.1016/j.addr.2007.05.010. [4] N. Blagden, M. de Matas, P.T. Gavan, P. York, Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates, Adv. Drug Deliv. Rev. 59 (2007) 617–630, https://doi.org/10.1016/j.addr.2007.05.011. [5] D.J. Good, R.H. Naír, Solubility advantage of pharmaceutical cocrystals, Cryst. Growth Des. 9 (2009) 2252–2264, https://doi.org/10.1021/cg801039j. [6] Y. Huang, G. Kuminek, L. Roy, K.L. Cavanagh, Q. Yin, N. Rodriguez-Hornedo, Cocrystal solubility advantage diagrams as a means to control dissolution, supersaturation, and precipitation, Mol. Pharm. (2019). [7] S.L. Childs, P. Kandi, S.R. Lingireddy, Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability, Mol. Pharm. 10 (2013) 3112–3127, https://doi.org/10.1021/mp400176y. [8] N. Qiao, K. Wang, W. Schlindwein, A. Davies, M. Li, In situ monitoring of carbamazepine-nicotinamide cocrystal intrinsic dissolution behaviour, Eur. J. Pharm. Biopharm. 83 (2013) 415–426, https://doi.org/10.1016/j.ejpb.2012.10.005. [9] H. Yamashita, C.C. Sun, Harvesting potential dissolution advantages of soluble cocrystals by depressing precipitation using the common coformer effect, Cryst. Growth Des. 16 (2016) 6719–6721, https://doi.org/10.1021/acs.cgd.6b01434. [10] K. Sugano, Aqueous boundary layers related to oral absorption of a drug: from dissolution of a drug to carrier mediated transport and intestinal wall metabolism, Mol. Pharm. 7 (2010) 1362–1373, https://doi.org/10.1021/mp1001119. [11] D. Murphy, F. Rodríguez -Cintrón, B. Langevin, R.C. Kelly, N. Rodriguez-Hornedo, Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder, Int. J. Pharm. 246 (2002) 121–134. [12] K. Shiraki, N. Takata, R. Takano, Y. Hayashi, K. Terada, Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds, Pharm. Res. (N. Y.) 25 (2008) 2581–2592, https://doi.org/10. 1007/s11095-008-9676-2. [13] M.S. Jasani, D.P. Kale, I.P. Singh, A.K. Bansal, Influence of drug-polymer interactions on dissolution of thermodynamically highly unstable cocrystal, Mol. Pharm. 16 (2019) 151–164, https://doi.org/10.1021/acs.molpharmaceut.8b00923. [14] R. Salas-z, C. Rodr, H. Höpfl, H. Morales-rojas, S. Obdulia, P. Rodr, Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers, (2019). [15] M. Yoshimura, M. Miyake, T. Kawato, M. Bando, M. Toda, Y. Kato, T. Fukami, T. Ozeki, Impact of the dissolution profile of the cilostazol cocrystal with supersaturation on the oral bioavailability, Cryst. Growth Des. 17 (2017) 550–557, https://doi.org/10.1021/acs.cgd.6b01425. [16] T. Uekusa, K. Sugano, Precipitation behavior of pioglitazone on the particle surface of hydrochloride salt in biorelevant media, J. Pharmaceut. Biomed. Anal. 161 (2018), https://doi.org/10.1016/j.jpba.2018.08.028. [17] J. Oki, D. Watanabe, T. Uekusa, K. Sugano, Mechanism of supersaturation suppression in dissolution process of acidic drug salt, Mol. Pharm. 16 (2019) 1669–1677, https://doi.org/10.1021/acs.molpharmaceut.9b00006. [18] S.L. Childs, N. Rodríguez -Hornedo, L.S. Reddy, A. Jayasankar, C. Maheshwari, L. McCausland, R. Shipplett, B.C. Stahly, Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of
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Solution-mediated phase transformation at particle surface during cocrystal dissolution
T
Maaya Omori, Taiga Uekusa, Jumpei Oki, Daisuke Inoue, Kiyohiko Sugano∗ Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga, 525-8577, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Cocrystal Carbamazepine Supersaturation Non-sink Dissolution test Induction time Mean diffusion time
In this study, we investigated solution-mediated phase transformation (SMPT) during cocrystal particle dissolution. When the solubility of a cocrystal is higher than that of the free form, the concentration of the free form can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Therefore, SMPT may occur either in the bulk phase or at the particle surface (PS-SMPT). Carbamazepine - glutaric acid cocrystal (CBZGLA) was used as a model cocrystal. Dissolution tests were performed under a non-sink condition. The residual particles were analyzed by polarized light microscopy (PLM), scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. Solvent-shift bulk phase precipitation tests and real-time PLM observation of PS-SMPT were also performed. In the dissolution test, little or no supersaturation was observed. CBZ-GLA particles rapidly and completely transformed to aggregates of CBZ dihydrate (CBZ DH) (> 95% within 3 min). The outer shape of the aggregates preserved that of initial CBZ-GLA particles, but distinctly differed from CBZ DH precipitated from the bulk phase. Real-time PLM observation revealed that PS-SMPT started within several seconds after contact with the medium. These results suggested that CBZ-GLA particles transformed to the aggregates of CBZ DH via PS-SMPT.
1. Introduction
formation may induce crystal lattice disorder to promote crystallization of a free form [11]. Furthermore, supersaturation characteristics cannot be evaluated under a sink condition. Non-sink dissolution tests have been used to assess the dissolution of cocrystal particles and the subsequent supersaturation and precipitation of the free form drug [6,12]. It has often been implicitly assumed that the free form precipitates from the supersaturated bulk phase after the dissolution of cocrystal particles. However, during the dissolution process, drug molecules diffuse through the unstirred water layer (UWL) adjacent to the particle to reach the bulk phase, depending on the concentration gradient around the particle. When a cocrystal shows a higher solubility than its free form, the free drug concentration can be markedly supersaturated at the dissolving cocrystal surface, leading to SMPT at the particle surface. Therefore, in a non-sink dissolution test of cocrystal particles, SMPT may occur either in the bulk phase or at the particle surface (BP-SMPT and PS-SMPT, respectively). A good understanding of SMPT during particle dissolution is required to develop an appropriate cocrystal formulation. However, in most literature, BPSMPT and PS-SMPT have been discussed ambiguously [13,14]. So far, based on limited experimental data, only a few reports speculated that cocrystal particles transformed to a free form via PS-SMPT during cocrystal particle dissolution [6,13,15]. To the best of our knowledge,
Recent drug candidates tend to be poorly soluble in aqueous media [1,2]. These drug candidates often show incomplete, variable, and less than dose proportional oral absorption. To increase the concentration of drug molecules dissolved in the gastrointestinal fluid, a poorly soluble drug candidate is often converted to a supersaturable active pharmaceutical ingredient (sAPI), such as cocrystals, salts, metastable crystal forms, and amorphous solid forms [3,4]. Cocrystal formation can transiently increase the concentration of a drug by orders of magnitude [5]. However, this transiently high concentration presents a risk for solution-mediated phase transformation (SMPT) to a free form during the dissolution process [6]. Previously, the dissolution mechanism of cocrystals has been mainly investigated using intrinsic dissolution tests (rotating disk or static disk method) under a sink condition. Several reports showed that the surface of a cocrystal disk converted to a free form via SMPT [7–9]. However, it is not clear whether SMPT observed on the disk surface also takes place at the particle level. The size of a disk (> 1 mm) is significantly greater than that of drug particles (usually < 0.1 mm). Hydrodynamics around a disk could be significantly different from that around a suspended particle [10]. High compression pressure applied during disk ∗
Corresponding author. E-mail address: [email protected] (K. Sugano).
https://doi.org/10.1016/j.jddst.2020.101566 Received 9 January 2020; Received in revised form 31 January 2020; Accepted 31 January 2020 Available online 06 February 2020 1773-2247/ © 2020 Elsevier B.V. All rights reserved.
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the small intestine [20]. The dose/fluid volume ratio was set to reflect the clinical dose (200 mg) and the intestinal fluid volume (50–250 mL) [21,22]. The paddle rotation speed was set to 100 rpm. Dissolution samples (0.40 mL) were withdrawn, filtered, and diluted by ethanol at specified time intervals (15, 30, 60, 120, 240, 360, and 1440 min). CBZ concentration was determined as described above. Dissolution tests were performed in triplicate. In a separate dissolution test, residual particles were collected at 1, 3, 10 and 30 min by vacuum filtration and analyzed by polarized light microscope (PLM, Olympus CX-43, Olympus Corporation, Tokyo, Japan), scanning electron microscope (SEM, TM-1000, Hitachi HighTechnologies Corporation, Tokyo, Japan), PXRD, and DSC.
detailed experimental evidences supporting PS-SMPT of cocrystals have not been reported. The purpose of the present study was to investigate SMPT of cocrystal particles during dissolution. Carbamazepine - glutaric acid cocrystal (CBZ-GLA) was used as a model drug. Previously, the surface of a CBZ-GLA disk was reported to convert to CBZ dihydrate (CBZ DH, thermodynamically most stable in aqueous media) during the rotating disk dissolution test [9]. In the present study, detailed analyses of the residual particles in non-sink dissolution tests were performed. In addition, solvent shift precipitation tests were performed to differentiate BP-SMPT from PS-SMPT. Furthermore, we directly observed SMPT of CBZ-GLA particles using a novel microscopic technique we recently developed [16,17].
2.2.5. Solvent-shift precipitation test Solvent-shift precipitation tests were performed using the same apparatus, dissolution medium, and paddle rotation speed with the non-sink dissolution test [23]. A concentrated dimethylacetamide solution of CBZ AH (0.5 mL) was added to blank FaSSIF at 37 °C. The initial bulk phase concentration was set to 2.1–2.4 mM. Samples were withdrawn, filtered, and diluted by ethanol at specified time intervals (0, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 1440 min). CBZ concentration was determined as described above. Solvent-shift precipitation tests were performed in triplicate.
2. Materials and methods 2.1. Materials Carbamazepine (anhydrous, form III) (CBZ AH), glutaric acid (GLA), NaH2PO4 2H2O, NaCl, 8 N NaOH, and ethanol were purchased from Wako Pure Chemical Industries, Ltd (Osaka, Japan). 2.2. Methods 2.2.1. Preparation of carbamazepine dihydrate and glutaric acid cocrystal CBZ DH was prepared by suspending CBZ AH in distilled water with vigorous stirring for 30 h. The resulting crystals were harvested by vacuum filtration. CBZ-GLA 1:1 cocrystal was prepared as previously reported [18]. CBZ AH (14.2 g) and GLA (4.0 g) were added to acetonitrile (150 mL) in a glass beaker and warmed at 60 °C. The solution was then stored at room temperature (25 ± 2 °C) for 7 days. The CBZ-GLA particles were harvested by vacuum filtration. The average size of CBZ-GLA particles was about 27 μm (determined by microscopic image analysis using ImageJ) [19]. The solid forms of CBZ DH and CBZ-GLA were confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) (see the PXRD and DCS sections).
2.2.6. Real-time polarized light microscope observation of PS-SMPT The experimental procedures of real-time PLM observation have been previously reported in detail [16]. In brief, CBZ-GLA particles (0.2–0.4 mg) were placed on a slide glass and covered with another slide glass. These two slide glasses were tightly pinched by using two binder clips to immobilize the particles between the slide glasses. The sample temperature was maintained at 37 °C by a glass plate heater (BLAST Inc., Kanagawa, Japan). Blank FaSSIF (30 μL) was penetrated between the slide glasses by capillary action from the side of the slide glass using a micropipette under a polarized light microscope. 3. Results 3.1. Dissolution profiles of carbamazepine – glutaric acid cocrystal (CBZGLA) and carbamazepine dihydrate (CBZ DH) under non-sink condition
2.2.2. Powder X-ray diffraction Samples were ground with a mortar and pestle prior to PXRD analysis. A sample was placed on a zero-diffraction plate and analyzed by PXRD (Rigaku Ultima IV, Rigaku corporation, Tokyo, Japan). Data was collected from 5 to 35° (2θ) at a step size of 0.02° and scanning speed of 10 deg/min with Cu Kα radiation generated at 40 mA and 40 kV. For the quantification of CBZ-GLA and CBZ DH in the dissolution test, a standard curve was prepared using the physical mixtures of CBZ-GLA and CBZ DH (0, 5, 20, 40, 80 and 100% of CBZ-GLA, r2 = 0.95). The percentage of CBZ-GLA was calculated from the peaks at 12.3° and 13.6° for CBZ DH and CBZ-GLA, respectively.
The time course profiles of CBZ concentration dissolved in the bulk phase (CCBZ, bulk) are shown in Fig. 1. The amount of CBZ added to the medium was 50 mg in 50 mL (as of CBZ free form, molecular
2.2.3. Differential scanning calorimetry The sample was placed in an aluminum pan (non-sealed) and analyzed by DSC at 10 °C/min under nitrogen gas (DSC60 plus, Shimazu Corporation Kyoto, Japan). The residual percentage of CBZ-GLA was calculated from the enthalpy of melting at 126 °C. A standard curve was prepared using the physical mixtures of CBZ-GLA and CBZ DH (0, 5, 20, 40, 80 and 100% of CBZ-GLA, r2 = 0.94). 2.2.4. Non-sink dissolution test The dissolution, supersaturation, and precipitation profiles of CBZGLA and CBZ DH were evaluated by a mini-paddle dissolution test under a non-sink condition (NTR-6200AC, Toyama Sangyo Co., Ltd., Osaka, Japan). CBZ particles (0.21 mmol, equivalent to 50 mg CBZ AH) were added to the fasted state simulated intestinal fluid without bile micelle (blank FaSSIF, 29 mM phosphate, 105 mM NaCl, pH 6.5, 50 mL) at 37 °C [20]. pH 6.5 was chosen because it is the representative pH of
Fig. 1. Dissolution profiles of CBZ-GLA and CBZ DH in blank FaSSIF for 0–4 h (mean ± S.D., n = 3). CBZ concentration reached a plateau after 4–6 h for both CBZ-GLA and CBZ DH (data not shown). 2
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Fig. 2. PXRD patterns of initial and residual particles in the non-sink dissolution test. Fig. 4. PLM and SEM images of initial and residual particles after 10 min in the non-sink dissolution test. (A) PLM, (B) SEM.
weight = 236). Therefore, the theoretical maximum CCBZ, bulk was 4.2 mM. Due to rapid dissolution, it was difficult to compare the initial dissolution rates. In the case of CBZ DH, CCBZ, bulk reached a plateau at 0.90 ± 0.02 mM after 4–6 h. This value is similar to the equilibrium solubility of CBZ DH at 37 °C reported in the literature [11,24]. In the case of CBZ-GLA, CCBZ, bulk showed little or no supersaturation, reaching a plateau at 0.93 ± 0.02 mM after 4–6 h. The residual particles were analyzed by powder X-ray diffraction (PXRD) (Fig. 2), differential scanning calorimetry (DSC) (Fig. 3), polarized light microscopy (PLM) (Fig. 4A), and scanning electron microscopy (SEM) (Fig. 4B). The residual particles were collected from the dissolution medium at each time point and immediately separated from the fluid to avoid solid form transformation before analysis. The residual percentage of CBZ-GLA was quantified by PXRD and DCS using the standard curves from the physical mixtures of CBZ-GLA and CBZ DH (r2 > 0.94) (Fig. 5). When using PXRD for quantification, the diffraction pattern may only reflect the residual percentage of CBZGLA at the particle surface. In addition, the effect of preferred orientation may interfere quantification, even when a sample is well ground before analysis. Therefore, the residual percentage of CBZ-GLA was quantified by both PXRD and DSC. CBZ-GLA rapidly and almost completely transformed to CBZ DH during the dissolution test (> 95% within 3 min). PLM and SEM images suggested that CBZ-GLA particles transformed to aggregates of needle-like crystals of CBZ DH while retaining the outer shape of the initial particle (Fig. 5).
Fig. 5. Residual percentage of CBZ-GLA in the non-sink dissolution test measured by DSC and PXRD.
3.2. Precipitation from the bulk phase The precipitation profiles of CBZ DH in the solvent-shift precipitation tests are shown in Fig. 6. After the addition of concentrated CBZ, the bulk phase became a homogeneous transparent solution, followed by precipitation of CBZ-DH. The critical supersaturation concentration for CBZ DH crystallization in the bulk phase was above 2.1 mM for the time scale of several hours (Fig. 6A). The induction time (tind) was calculated as the intercept of the precipitation line and the initial CCBZ, bulk value (CCBZ, bulk, ini). Fig. 6B shows the relationship between the induction time (tind) and the initial supersaturation ratio (S = CCBZ, bulk, ini/SCBZ DH (SCBZ DH: the equilibrium solubility of CBZ DH (0.90 mM))) (Supplemental information, Table S1). A linear correlation was observed between (log S)−2 and tind [25]. The precipitated CBZ DH particles were needle-like crystals with smooth surfaces without aggregation (Fig. 7) (the solid form was confirmed by PXRD and DSC (Supplemental information, Fig. S1).
3.3. Real-time solution-mediated phase separation observed under polarized light microscope (PLM) Fig. 3. DSC patterns of initial and residual particles in the non-sink dissolution test.
The real-time PLM images of CBZ-GLA after contact with blank 3
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Fig. 6. Results of bulk phase solvent-shift precipitation test. (A) Concentration time profiles (mean ± S.D., n = 3), (B) relationship between the initial supersaturation ratio (S) and the induction time (tind). The insert in (A) is the enlarged figure from 0 to 4 h.
to CBZ DH (> 95% within 3 min) (Figs. 2–4). Therefore, there is little or no CBZ-GLA dissolution after 3 min. The results of the solvent-shift precipitation tests showed that, once CBZ was dissolved in the bulk phase, CCBZ, bulk would maintain supersaturated concentration without precipitation for several hours up to 2.1 mM (Fig. 6A). Therefore, there was a concentration window (from 0.9 to 2.1 mM), which was sufficient to observe supersaturation in the bulk phase. In addition, the residual particles in the non-sink dissolution test were aggregates of CBZ DH crystals that preserved the outer shape of the initial CBZ-GLA particles (Fig. 4), but were distinctly different from CBZ DH precipitated from the bulk phase (Fig. 7). Therefore, it is unlikely that CBZ DH precipitated from the bulk phase. Rather, preservation of the outer shape of the initial particles suggests that CBZ-GLA particles transformed to CBZ DH via PS-SMPT. Furthermore, the real-time PLM observation suggested that SMPT occurred at the particle surface within several seconds after contacted with the medium (Fig. 8A). These experimental results provided further evidence to support PS-SMPT. In-line (in situ) solid form analysis, such as in situ Raman spectroscopy, may provide more direct evidence of PS-SMPT. This method has been used to observe SMPT at the fixed disk surface [8]. However, it is difficult to apply this method to rapid SMPT of suspended particles in an agitated medium. Instead of in-line analysis of suspended particles, we observed PS-SMPT in real-time under a polarized light microscope. Theoretically, when the precipitation induction time is shorter than the time scale of a process, free form precipitation takes place during that process. The time scale of diffusion across UWL adjacent to a particle (tdiff,UWL) can be approximately calculated as,
FaSSIF are shown in Fig. 8A. The surface texture of the CBZ-GLA particles started to change within several seconds after contact with blank FaSSIF. The appearance of the particles was similar to that recovered from the non-sink dissolution test. 4. Discussion As mentioned in the introduction, during the dissolution of cocrystal particles, solution-mediated phase separation (SMPT) may occur either in the bulk phase (BP-SMPT) or at the particle surface (PS-SMPT). It has often been implicitly assumed that the free form precipitates from the supersaturated bulk phase after the dissolution of cocrystal particles. However, since the concentration of the free form can be markedly supersaturated at the dissolving cocrystal surface, rapid precipitation of the free form can also occur at the cocrystal surface [29]. Therefore, in a non-sink dissolution test of cocrystal particles, it is anticipated that transient supersaturation would be observed in the bulk phase in the case of BP-SMPT, but not in the case of PS-SMPT. In the non-sink dissolution test of CBZ-GLA particles, little or no supersaturation was observed in the bulk phase (Fig. 1), suggesting that CBZ-GLA particles transformed to CBZ DH via PS-SMPT [6,13,15]. However, this result is not sufficient to firmly support PS-SMPT due to the following reasons: (I) the concentration - time profile observed in the bulk phase may be superficially caused by the balance of the dissolution of CBZ-GLA and the precipitation of CBZ DH, (II) the critical supersaturation ratio may be close to 1, and there may be no concentration window to observe supersaturation in the bulk phase (III), BP-SMPT may occur before the first sampling time point, and (IV) the solid form of the particles was identified off-line, so that solid form transformation might have been occurred before analysis. In this study, CBZ-GLA rapidly and almost completely transformed
tdiff , UWL ≈
h2 2D
(1)
where D is the diffusion co efficient, and h is the thickness of the UWL.
Fig. 7. PLM and SEM images of CBZ DH particles recovered from the bulk phase solvent-shift precipitation test. (A) PLM, (B) SEM. 4
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Fig. 8. CBZ-GLA to CBZ DH transformation. (A) Real-time PLM images of CBZ-GLA after contact with blank FaSSIF, (B) sectional schematic illustration of PS-SMPT for CBZ-GLA.
passive film of the free acid was formed on the particle surface in the early stage of dissolution to suppress the dissolution of the salt [17]. PSSMPT was also observed for pioglitazone HCl and tosufloxacin mesylate [31,32]. Thus, PS-SMPT can commonly occur among salts and cocrystals. PS-SMPT of other sAPIs, such as amorphous and metastable crystal forms, is under investigation. To induce supersaturation in the bulk phase, it is important to fine tune the solubility of a cocrystal to avoid PS-SMPT [15]. In addition, drug formulations need to be optimized to effectively utilize the solubilization potential of a cocrystal. Previously, Shiraki et al. reported that particle size reduction was effective in inducing a supersaturated drug concentration from a cocrystal [12]. Particle size reduction can reduce tdiff,UWL so that to increase the amount of drug molecules reaching the bulk phase. The addition of a polymer or a surfactant would be also effective [6,7,33–38]. The effects of cocrystal solubility, particle size, and precipitation inhibitors on PS-SMPT is under investigation. In conclusion, this study provided more conclusive evidence supporting PS-SMPT during cocrystal dissolution. Detailed PLM and SEM observations of residual particles in a dissolution test and real-time microscopic observation are useful to investigate PS-SMPT. Solventshift precipitation tests provide the characteristics of BP-SMPT. A good understanding of PS-SMPT during particle dissolution is of great importance in developing cocrystals.
In the case of small particles (particle radius (rp) < 30 μm), h can be approximated as h = rp [26,27]. The average radius of the CBZ-GLA particles was 14 μm. The diffusion coefficient of CBZ was estimated from the molecular weight to be 8.3 × 10−6 cm2/s [28]. From these data and Eq. (1), the tdiff,UWL value was estimated to be 110 ms. The mean induction time in the UWL (tind,UWL) should be smaller than this value for PS-SMPT. The tind,UWL value can be roughly calculated from the solubility of the cocrystal and the tind – log S relationship (Fig. 6B). Based on the solubility of CBZ-GLA cocrystal (54 mM) [5], the tind,UWL value was estimated to be 1.6 ms. Although extrapolating the tind value at 54 mM from the data in the range of 2.1–2.4 mM might be inaccurate, the estimated tind,UWL value was 2 orders of magnitude shorter than the tdiff,UWL value and thus did not negate PS-SMPT at least. The results of the present study were in good agreement with the previous result showing that the surface of a CBZ-GLA disk was transformed to CBZ-DH during an intrinsic dissolution test [29]. However, the CBZ-GLA disk was not completely transformed to CBZ DH after 10 min (based on PXRD analysis). In contrast, in the present study, CBZGLA particles were almost completely transformed to CBZ DH within 3 min. Therefore, the rate of SMPT at the particle surface might be faster than that at the disk surface. PS-SMPT proceeded inside the particle, probably because there were pores between the precipitated CDZ DH crystals on the surface (Fig. 8B). Yamashita et al. suggested that CBZ-GLA can be a self-template to enhance CBZ DH crystallization on the surface of CBZ-GLA [30]. This effect may also have accelerated PS-SMPT of CBZ-GLA particles. Recently, Huang et al. investigated the dissolution, supersaturation, and precipitation profiles of the indomethacin – saccharin cocrystal under a non-sink condition [6]. Microscopic observation of residual particles suggested that indomethacin free acid crystallized on the cocrystal surface during the dissolution process of cocrystals. However, supersaturation was observed in the bulk phase and precipitation occurred slowly (> 1 h). Yoshimura et al. have also suggested PS-SMPT of cocrystals, but solely based on the dissolution profile [15]. Therefore, it was not clear whether precipitation occurred via either PS-SMPT or BPSMPT in these studies. In the present study, together with the PXRD and DSC analyses of residual particles, the SEM and PLM observations provided further evidences supporting PS-SMPT. The result of the solvent-shift precipitation test suggested that BP-SMPT was highly unlikely. The result of the real-time PS-SMPT observation also supported PS-SMPT. Recently, we reported that PS-SMPT also occurred for drug salts. In the case of diclofenac sodium, in an acidic medium (pH < < pKa), a
CRediT authorship contribution statement Maaya Omori: Data curation, Validation, Writing - review & editing. Taiga Uekusa: Data curation. Jumpei Oki: Data curation. Daisuke Inoue: Supervision, Validation. Kiyohiko Sugano: Supervision, Funding acquisition, Writing - original draft. Declaration of competing interest The Author(s) declare(s) that they have no conflicts of interest to disclose. Acknowledgement This research was partly supported by AMED under Grant Number JP17ak0101074. Part of this study was presented at APSTJ annual meeting in Toyama, Japan (May, 2019). 5
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Appendix A. Supplementary data
carbamazepine, CrystEngComm 10 (2008) 856–864. [19] C.A. Schneider, W.S. Rasband, K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis, Nat. Methods 9 (2012) 671. [20] E. Galia, E. Nicolaides, D. Hörter, R. Löbenberg, C. Reppas, J.B. Dressman, Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs, Pharm. Res. (N. Y.) 15 (1998) 698–705. [21] C. Schiller, C.P. Fröhlich, T. Giessmann, W. Siegmund, H. Mönnikes, N. Hosten, W. Weitschies, Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging, Aliment. Pharmacol. Ther. 22 (2005) 971–979, https://doi.org/10.1111/j.1365-2036.2005.02683.x. [22] M. Grimm, M. Koziolek, M. Saleh, F. Schneider, G. Garbacz, J.P. Kühn, W. Weitschies, Gastric emptying and small bowel water content after administration of grapefruit juice compared to water and isocaloric solutions of glucose and fructose: a four-way crossover MRI pilot study in healthy subjects, Mol. Pharm. 15 (2018) 548–559, https://doi.org/10.1021/acs.molpharmaceut.7b00919. [23] S. Ozaki, Population balance model for simulation of the supersaturation–precipitation behavior of drugs in supersaturable solid forms, J. Pharm. Sci. 108 (2019) 260–267, https://doi.org/10.1016/j.xphs.2018.07.027. [24] Y. Kobayashi, S. Ito, S. Itai, K. Yamamoto, Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate, Int. J. Pharm. 193 (2000) 137–146. [25] S. Ozaki, T. Minamisono, T. Yamashita, T. Kato, I. Kushida, Supersaturation–nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms, J. Pharm. Sci. 101 (2012) 214–222. [26] R.J. Hintz, K.C. Johnson, The effect of particle size distribution on dissolution rate and oral absorption, Int. J. Pharm. 51 (1989) 9–17. [27] K. Sugano, Theoretical comparison of hydrodynamic diffusion layer models used for dissolution simulation in drug discovery and development, Int. J. Pharm. 363 (2008), https://doi.org/10.1016/j.ijpharm.2008.07.002. [28] A. Avdeef, Leakiness and size exclusion of paracellular channels in cultured epithelial cell monolayers-interlaboratory comparison, Pharm. Res. (N. Y.) 27 (2010) 480–489, https://doi.org/10.1007/s11095-009-0036-7. [29] H. Yamashita, C.C. Sun, Improving dissolution rate of carbamazepine-glutaric acid cocrystal through solubilization by excess coformer, Pharm. Res. (N. Y.) 35 (2018), https://doi.org/10.1007/s11095-017-2309-x. [30] H. Yamashita, C.C. Sun, Self-templating accelerates precipitation of carbamazepine dihydrate during the dissolution of a soluble carbamazepine cocrystal, CrystEngComm 19 (2017) 1156–1159, https://doi.org/10.1039/c6ce02418a. [31] T. Uekusa, K. Sugano, Effect of buffer capacity on dissolution and supersaturation profiles of poorly soluble drug salt, APSJT Annu. Meet, 2019, p. 236. Toyama. [32] Y. Tanaka, K. Sugano, Effect of buffer capacity on supersaturation profiles of tosufloxacin tosilate, APSTJ Annu. Meet, 2019, p. 263. Toyama. [33] M. Li, S. Qiu, Y. Lu, K. Wang, X. Lai, M. Rehan, Investigation of the effect of hydroxypropyl methylcellulose on the phase transformation and release profiles of carbamazepine-nicotinamide cocrystal, Pharm. Res. (N. Y.) 31 (2014) 2312–2325, https://doi.org/10.1007/s11095-014-1326-2. [34] M. Guo, K. Wang, N. Hamill, K. Lorimer, M. Li, Investigating the influence of polymers on supersaturated flufenamic acid cocrystal solutions, Mol. Pharm. 13 (2016) 3292–3307, https://doi.org/10.1021/acs.molpharmaceut.6b00612. [35] C. Wang, Q. Tong, X. Hou, S. Hu, J. Fang, C.C. Sun, Enhancing bioavailability of dihydromyricetin through inhibiting precipitation of soluble cocrystals by a crystallization inhibitor, Cryst. Growth Des. 16 (2016) 5030–5039, https://doi.org/10. 1021/acs.cgd.6b00591. [36] A. Alhalaweh, H.R.H. Ali, S.P. Velaga, Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media, Cryst. Growth Des. 14 (2014) 643–648, https://doi.org/10.1021/cg4015256. [37] M. Ullah, I. Hussain, C.C. Sun, The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance, Drug Dev. Ind. Pharm. 42 (2016) 969–976, https://doi.org/10.3109/03639045.2015. 1096281. [38] S. Qiu, J. Lai, M. Guo, K. Wang, X. Lai, U. Desai, N. Juma, M. Li, Role of polymers in solution and tablet-based carbamazepine cocrystal formulations, CrystEngComm 18 (2016) 2664–2678, https://doi.org/10.1039/c6ce00263c.
Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jddst.2020.101566. References [1] K. Sugano, A. Okazaki, S. Sugimoto, S. Tavornvipas, A. Omura, T. Mano, Solubility and dissolution profile assessment in drug discovery, Drug Metabol. Pharmacokinet. 22 (2007), https://doi.org/10.2133/dmpk.22.225. [2] A.M. Thayer, C. Houston, Finding solutions. Custom manufacturers take on drug solubility issues to help pharmaceutical firms move products through development, Chem. Eng. News 88 (2010) 13–18, https://doi.org/10.1016/j.jenvp.2009.05.001. [3] A.T.M. Serajuddin, Salt formation to improve drug solubility, Adv. Drug Deliv. Rev. 59 (2007) 603–616, https://doi.org/10.1016/j.addr.2007.05.010. [4] N. Blagden, M. de Matas, P.T. Gavan, P. York, Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates, Adv. Drug Deliv. Rev. 59 (2007) 617–630, https://doi.org/10.1016/j.addr.2007.05.011. [5] D.J. Good, R.H. Naír, Solubility advantage of pharmaceutical cocrystals, Cryst. Growth Des. 9 (2009) 2252–2264, https://doi.org/10.1021/cg801039j. [6] Y. Huang, G. Kuminek, L. Roy, K.L. Cavanagh, Q. Yin, N. Rodriguez-Hornedo, Cocrystal solubility advantage diagrams as a means to control dissolution, supersaturation, and precipitation, Mol. Pharm. (2019). [7] S.L. Childs, P. Kandi, S.R. Lingireddy, Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability, Mol. Pharm. 10 (2013) 3112–3127, https://doi.org/10.1021/mp400176y. [8] N. Qiao, K. Wang, W. Schlindwein, A. Davies, M. Li, In situ monitoring of carbamazepine-nicotinamide cocrystal intrinsic dissolution behaviour, Eur. J. Pharm. Biopharm. 83 (2013) 415–426, https://doi.org/10.1016/j.ejpb.2012.10.005. [9] H. Yamashita, C.C. Sun, Harvesting potential dissolution advantages of soluble cocrystals by depressing precipitation using the common coformer effect, Cryst. Growth Des. 16 (2016) 6719–6721, https://doi.org/10.1021/acs.cgd.6b01434. [10] K. Sugano, Aqueous boundary layers related to oral absorption of a drug: from dissolution of a drug to carrier mediated transport and intestinal wall metabolism, Mol. Pharm. 7 (2010) 1362–1373, https://doi.org/10.1021/mp1001119. [11] D. Murphy, F. Rodríguez -Cintrón, B. Langevin, R.C. Kelly, N. Rodriguez-Hornedo, Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder, Int. J. Pharm. 246 (2002) 121–134. [12] K. Shiraki, N. Takata, R. Takano, Y. Hayashi, K. Terada, Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds, Pharm. Res. (N. Y.) 25 (2008) 2581–2592, https://doi.org/10. 1007/s11095-008-9676-2. [13] M.S. Jasani, D.P. Kale, I.P. Singh, A.K. Bansal, Influence of drug-polymer interactions on dissolution of thermodynamically highly unstable cocrystal, Mol. Pharm. 16 (2019) 151–164, https://doi.org/10.1021/acs.molpharmaceut.8b00923. [14] R. Salas-z, C. Rodr, H. Höpfl, H. Morales-rojas, S. Obdulia, P. Rodr, Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers, (2019). [15] M. Yoshimura, M. Miyake, T. Kawato, M. Bando, M. Toda, Y. Kato, T. Fukami, T. Ozeki, Impact of the dissolution profile of the cilostazol cocrystal with supersaturation on the oral bioavailability, Cryst. Growth Des. 17 (2017) 550–557, https://doi.org/10.1021/acs.cgd.6b01425. [16] T. Uekusa, K. Sugano, Precipitation behavior of pioglitazone on the particle surface of hydrochloride salt in biorelevant media, J. Pharmaceut. Biomed. Anal. 161 (2018), https://doi.org/10.1016/j.jpba.2018.08.028. [17] J. Oki, D. Watanabe, T. Uekusa, K. Sugano, Mechanism of supersaturation suppression in dissolution process of acidic drug salt, Mol. Pharm. 16 (2019) 1669–1677, https://doi.org/10.1021/acs.molpharmaceut.9b00006. [18] S.L. Childs, N. Rodríguez -Hornedo, L.S. Reddy, A. Jayasankar, C. Maheshwari, L. McCausland, R. Shipplett, B.C. Stahly, Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of
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