Dissolution Behavior of the Crystalline Inclusion Complex Formed by

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The Dissolution Behavior of the Crystalline Inclusion Complex Formed by Drug Diflunisal and Poly(#-caprolactone) Zhi Zhong, Xiaotong Yang, Baohua Guo, Jun Xu, and Yanbin Huang Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01578 • Publication Date (Web): 23 Nov 2016 Downloaded from http://pubs.acs.org on November 28, 2016

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Crystal Growth & Design

The Dissolution Behavior of the Crystalline Inclusion Complex Formed by Drug Diflunisal and Poly(ε-caprolactone) Zhi Zhong, Xiaotong Yang, Bao-hua Guo, Jun Xu*, and Yanbin Huang* Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing 100084, China

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ABSTRACT

Multi-component crystals provide a promising strategy to modulate and optimize the dissolution behaviors of drugs, among which pharmaceutical co-crystals formed between drugs and small molecular co-formers have received much attention. Recent studies have shown that certain drugs can also form crystalline inclusion complexes (ICs) with linear polymers, representing a new sub-category of multi-component pharmaceutical crystals. In this study, we investigated in detail the dissolution behavior and the structure evolution of a crystalline inclusion complex formed by drug diflunisal (DIF) and hydrophobic poly(ε-caprolactone) (PCL). The dissolution profiles of DIF-PCL IC exhibited decreased solubility and dissolution rate compared with the pure DIF crystals at the low pH value. The PCL chains initially residing in the IC channels coalesced and formed crystalline but porous PCL shells on the IC particles during dissolution. These results demonstrated the possibility of using drug-PCL ICs to slow down the drug dissolution, and the in-situ formation of an interesting core-shell structure with a biodegradable PCL shell and a drug-PCL IC core.


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Introduction After the chemical structure of a drug is finalized, the selection of its specific physical form plays a key role in modulating its physicochemical properties such as the dissolution profile and stability, and consequently affects the absorption and efficacy of that drug1. So far, most of the drugs are developed using the most stable crystal polymorph of the pure drug molecule, its hydrates, or simple salts2. However, as more and more drugs possess challenging dissolution properties and when none of the aforementioned simple solid forms can achieve the desirable pharmaceutical profile, multi-component crystals provide an alternative approach for such drugs. For example, pharmaceutical co-crystals, which are crystalline molecular complexes formed between the drug molecule and other pharmaceutically acceptable compounds (i.e., co-formers), represents a promising strategy to modulate and optimize the dissolution behaviors of drugs3-5. Incorporation of the second component significantly alters the molecular packing of drugs, and the resulted pharmaceutical co-crystals have been shown to possess dramatically different dissolution profiles from those of the pure drug crystals6-8. More interestingly, it was found that while hydrophilic co-formers can improve the solubility and dissolution rate of poorly water soluble drugs, the use of hydrophobic co-formers can actually lower the solubility of drugs9-12. However, despite many studies on pharmaceutical co-crystals, the general structureproperty relationship of such multi-component crystals is not yet clearly understood, especially the dissociation and structural evolution of these multi-component crystals in the aqueous medium. In addition to the pharmaceutical co-crystals formed with small molecular co-formers, certain drug molecules were found to form crystalline inclusion complexes (ICs) with multiple


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types of linear polymers, including hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(ε-caprolactone) (PCL)13,14. In drug-polymer ICs, polymer chains of extended conformations reside in the parallel, isolated channels formed by drug molecules. The interactions between drug molecules and the guest polymer in ICs are mainly van der Waals forces (for the drug-polymer pairs studied so far), in contrast to the specific interactions (e.g., hydrogen bonds) commonly observed in pharmaceutical co-crystals. The guest polymers in ICs seem to mainly act as cavity fillers to stabilize the otherwise-maybe-unstable channel structure formed by the drug molecules. Therefore, isostructural ICs can be readily formed by simply changing the type and molecular weight of the guest polymers. This feature may provide a facile way to systematically modulate the physicochemical properties of ICs without substantially altering the crystal structure. Previously, we reported the dissolution profiles of ICs formed by poorly soluble drug griseofulvin and soluble PEG, and showed that the dissolution rate of the hydrophobic drug griseofulvin was significantly enhanced, and during the dissolution process the two components dissociated: the soluble PEG dissolved while the griseofulvin molecules precipitated in its own crystal form15. In contrast to the hydrophilic PEG polymer, here we are interested in the dissolution behaviors of the drug-polymer ICs formed with hydrophobic polymer poly(ε-caprolactone) (PCL), i.e., the diflunisal-PCL IC14. Similar to the aforementioned hydrophobic co-former effect, we hypothesize that the diflunisal-PCL IC will show slower dissolution rate than the diflunisal crystals. More interestingly, since PCL is almost insoluble in water, the release and precipitation of PCL from diflunisal-PCL IC during dissolution may lead to the in-situ formation of a PCL shell on the dissolving IC particles, which may represent a new mechanism to further slower the dissolution/release of the drug16,17. Diflunisal (DIF) is a non-steroid anti-inﬂammatory drug


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(NSAID), with pH dependent solubility and dissolution rate18, making it an interesting model compound for soluble drugs. In addition, recent studies have shown the potential of DIF in the treatment of familial amyloid polyneuropathy19,20. Therefore, DIF-PCL IC may be a new diflunisal crystal form with slower dissolution rate and possibly useful for developing an injectable, sustained-release DIF to improve the patient compliance in chronic uses. The molecular formula of DIF and PCL are shown in Figure 1, as well as the crystal structure of DIF-PCL IC as reported in our previous publication14. As mentioned above, the aqueous solubility of DIF shows a strong pH dependence due to the carboxylic acid group in its structure (pKa = 3.3)21, with the reported solubility at pH 6 being about 10 times of that at pH 4 18

. Therefore, in this study the dissolution experiments of DIF-PCL IC were conducted at both

pH 4.4 and pH 6.4 to study the pH effect on PCL in modulating the dissolution behavior of DIF. In addition, as there is possibility of solid phase transformation and supersaturation during dissolution tests, the dissolution tests were performed under both sink conditions (i.e., even if all the drug solid dissolves, the drug concentration in the dissolution media is still lower than its equilibrium solubility) and non-sink conditions (where excess drug solids would remain). For comparison, the dissolution behavior of DIF Form I, which is the thermodynamically stable, nonsolvated, non-salt form of DIF under the ambient condition22, was also tested under the same conditions. Based on the experimental results, a physical picture is proposed for the dissolution profiles of crystalline ICs with hydrophobic polymers.


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Figure 1. (a) Structure formula of DIF and PCL. (b) Crystal structure of DIF-PCL IC shown in the space-filling representation. The PCL chains are accommodated in the continuous channels along the crystallographic b-axis.

Experimental Section Materials Diflunisal (DIF Form I, 98% purity) and poly(ε-caprolactone) (PCL, Mn 10,000 Da) were both obtained from Sigma-Aldrich. All the solvents used in this study were AP grade and used without further purification. DIF-PCL IC was prepared using the method described in our previous publication14. To help identify the new crystal form appeared in certain dissolution


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experiments, crystal of DIF sodium salt was prepared following the method in literature23,24: 0. 25 g of DIF was added into 10 mL of 0.1 M aqueous sodium hydroxide solution. Afterwards, 20 mL of deionized water was gradually added to the solution and stirred until all the solids completely dissolved. The solution was then filtered (cellulose acetate-nitrocellulose membrane, 0.22 µm) and freeze dried (Alpha 1-2 LD plus, Christ), and white fibrous crystals were collected. Solubility & Dissolution Profiles The dissolution behavior of DIF-PCL IC and DIF Form I was studied in the phosphate-citrate buffer of pH 4.4 and 6.4. The buffer was prepared by mixing aqueous disodium hydrogen phosphate solution (0.2 M) and aqueous sodium citrate solution (0.1 M), with a volume ratio of 8.82:11.18 (for the pH 4.4 buffer) and 13.85:6.15 (for the pH 6.4 buffer). All the solid samples were gently ground and particles in the size range of 150-180 µm were collected via sieving and used in the dissolution tests. The dissolution profiles were tested by monitoring DIF concentration using a UV-vis spectrophotometer (Agilent-8453, Agilent Technologies) at room temperature. The absorbance-concentration curves of DIF in buffer at pH 4.4 and pH 6.4 were established using the absorption peak at wavelength 252 nm and 307 nm, respectively. At pH 4.4, sink-condition dissolution experiments were conducted by adding 13.0 mg DIF Form I or 14.4 mg DIF-PCL IC (containing 13.0 mg DIF equivalent) to 500 mL of pH 4.4 buffer. If all the drug solid dissolves, the DIF concentration will be about 25% of the equilibrium solubility of DIF Form I. Please be noted that this maximum concentration/solubility ratio (e.g., 25%) is higher than the one conventionally used to define the sink condition (i.e., 15% or 20%), and we use the word ‘sink condition’ here only to indicate that under this condition all the drug would dissolve at the final equilibrium state. The resultant suspension was stirred at a constant


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speed of 400 rpm (MS-PA, Scilogex). 3 mL of the suspension was removed from the dissolution media and replaced by 3 mL of pH 4.4 buffer at regular time intervals. The removed suspension was filtered (cellulose acetate-nitrocellulose membrane, 0.22 µm) and the first 1 mL of the filtrate was discarded. The UV-vis absorption spectra of the remaining filtrate were collected using a quartz cuvette with an optical length of 1 cm. The absorption peak at 252 nm was used to determine the DIF concentration. For non-sink condition dissolution experiments at the same pH value, 200.0 mg DIF Form I or 222.2 mg DIF-PCL IC (containing 200.0 mg DIF equivalent) was added to 500 mL phosphate-citrate buffer. The added solid amount represented 3.9 times of DIF solubility in the dissolution media. The filtrate collected at different time intervals was diluted five times before UV-vis test. At pH 6.4, 200.0 mg DIF Form I or 222.2 mg DIF-PCL IC (containing 200.0 mg DIF equivalent) was added to 500 mL of the buffer for sink-condition dissolution tests. If all the drug solid dissolves, the DIF concentration will be about 39% of the equilibrium solubility of the monosodium bis-diflunisal monohydrate crystal, which is the stable solid form at this pH (more on this in the later section). The filtrate collected at regular time intervals was diluted 5 times before UV-vis test. While for non-sink condition dissolution experiments at the same pH value, 400.0 mg DIF Form I or 444.4 mg DIF-PCL IC (containing 400.0 mg DIF equivalent) was added to 100 mL buffer. The added solid amount represented 3.9 times of the stable solid solubility in the dissolution media. The filtrate was diluted 25 times before UV-vis test. Other experimental conditions were the same as those at pH 4.4. The equilibrium solubilities of DIF Form I and DIF-PCL IC in the dissolution media were determined by the following procedure. Excess amounts of DIF Form I or DIF-PCL IC were suspended in the phosphate-citrate buffer and stirred for 4 days before filtration. The first 2


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mL of the filtrate was discarded and the remaining filtrate was diluted proper times to determine the DIF concentration by UV-vis. All the above experiments were repeated three times, and the residual solids were collected to confirm the solid identity. Powder X-ray Diffraction (PXRD) Samples for diffraction measurements were ground manually with an agate mortar and pestle, and then sieved through a 200 mesh screen before test. The tests were conducted using a Rigaku D/max-2500 X-ray diffractometer with Cu Kα radiation (1.54056 Å), at a scanning speed of 2° 2θ/min in the range 2θ = 2-45°. Differential Scanning Calorimetry (DSC) DSC measurements were performed on a Shimadzu DSC-60 differential scanning calorimeter. Temperature calibration was carried out using an indium metal standard before test. Powder samples (3-5 mg) were placed and sealed in aluminum pans and scanned from -15 °C to 240 °C at a heating rate of 10 °C/min. For the melt-crystallization of the coalesced PCL and raw PCL, the powder samples were first heated to 80 °C and remained at this temperature for 5 min then followed by cooling scans at different cooling rates. An empty pan was used as the reference. The samples were purged with a stream of nitrogen at 50 mL/min throughout the experiment. Simultaneous DTA-TGA Simultaneous DTA (differential thermal analysis)-TGA (thermogravimetric analysis) tests were conducted on a Shimadzu DTG-60 apparatus. Powder samples (7-10 mg) were placed in aluminum pans, and heated over the temperature range of 25-450 °C at a heating rate of 10 °C/min. Nitrogen gas of a flow rate of 50 mL/min was used to create an inert atmosphere. The


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temperature difference between the samples and the reference, as well as the weight loss of the samples, were recorded simultaneously. Nuclear Magnetic Resonance (1H-NMR) Solution 1H-NMR was used to characterize the chemical composition of the residual solids during dissolution. The samples were dissolved in deuterated chloroform and 1H-NMR spectra were collected using a JOEL JNM-ECA300 nuclear magnetic resonance spectrometer. Scanning Electron Microscopy (SEM) For SEM observation, DIF-PCL IC particles were removed from the dissolution media at different time intervals from the start of dissolution. The tests were conducted using a fieldemission microscope (SU8000, Hitachi), with an accelerating voltage of 10 kV (for undissolved and partially dissolved IC particles) and 5 kV (for coalesced PCL samples). Polarized Optical Microscopy (POM) Polarized optical microscope (BX41, Olympus) equipped with a digital camera (Moticam Pro 282A, Motic) was used to observe the changes in particle morphology during the dissolution of DIF- PCL IC. For the sink-condition dissolution experiments conducted at pH 4.4 and 6.4, 0.5 mL of the suspension was removed from the dissolution media at different time intervals, and dropped on a glass slide under the microscope. For in-situ observation of the formation of PCL shells on IC particles during dissolution, a small amount of IC particles was placed between two cover slips, which were then immersed in the phosphate-citrate buffer in a Petri dish. The morphology of a single particle was recorded at regular time intervals. Phase transformation of DIF-PCL IC and DIF Form I at pH 6.4 under non-sink conditions was observed in-situ by


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suspension of excess amounts of crystals in the phosphate-citrate buffer in a Petri dish and monitoring the changes of crystal morphology with time.

Results & Discussion Dissolution Profiles and Identities of the Residual Solids The powder dissolution profiles of DIF-PCL IC and DIF Form I are shown in Figure 2. It can be seen that both the solid forms exhibit pH dependent dissolution profiles, with the dissolution rate and the apparent plateau or peak solubility much higher at pH 6.4 than that at pH 4.4. At pH 4.4 under the sink condition, DIF-PCL IC showed a slower dissolution rate than DIF Form I crystals (Figure 2a), with only 50 wt% of the IC crystals dissolved after 4 h. The residual solid was found remain to be mainly the DIF-PCL IC crystals, plus a small amount of PCL crystals as confirmed by PXRD (Figure 3), DSC and 1H-NMR characterizations (Figure S1, S2). Similarly, under the non-sink conditions, the final residual solid for DIF-PCL IC at pH 4.4 was a mixture of the IC crystal and PCL crystal, as evidenced by the co-existence of the characteristic peaks from DIF-PCL IC (e.g., at 10.9°, 11.6° and 15.7° 2θ) and PCL crystals (e.g., at 21.6° and 22.2° 2θ) in the diffraction pattern (Figure 3b). No solid phase transformation was observed for DIF-PCL IC and DIF Form I even after 4 days in the dissolution media, suggesting that these two forms are likely thermodynamically stable when left alone at pH 4.4, respectively. The equilibrium solubility of DIF-PCL IC and DIF Form I was determined to be 50.3 ± 0.2 µg/mL and 102.5 ± 2.2 µg/mL, respectively. Therefore, at pH 4.4, DIF-PCL IC showed both lower solubility and slower dissolution rate than pure DIF crystals.


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Figure 2. Powder dissolution profiles of DIF-PCL IC and DIF Form I at pH 4.4 (a) and pH 6.4 (b) under both sink and non-sink conditions (N = 3). It should be noted that on the dissolution curves under sink conditions, the error bars were smaller than the data marks.


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Figure 3. (a) PXRD patterns of the residual solids removed from the pH 4.4 buffer after different time intervals under sink and non-sink conditions. Diffraction patterns of the raw materials are


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also included for comparison. The blue dashed lines indicate the characteristic peak locations of PCL crystals. (b) Part of the diffraction patterns was magnified to show more clearly the existence of the characteristic peaks from PCL crystals (e.g., at 21.6° and 22.2° 2θ) in the partially dissolved DIF-PCL IC samples. In contrast, at pH 6.4 under sink conditions, both DIF-PCL IC and DIF Form I dissolved rapidly and the drug concentrations reached the same plateau value within 30 min (Figure 2b). PXRD characterization of the residual solids revealed that the IC crystals completely dissolved within 4 h, leaving only crystalline PCL (Figure 4), which was further confirmed by DSC characterization (Figure S1). Under non-sink conditions at pH 6.4, both DIF-PCL IC and DIF Form I showed distinctly different dissolution behaviors compared with those at pH 4.4. As shown by the dissolution profiles (Figure 2b), high drug concentrations were generated by the rapid dissolution of DIFPCL IC within the first 20 min then followed by a sharp decrease in drug concentration to an apparent plateau value, suggesting the formation of new crystal. Under the same conditions, DIF Form I also displayed initial fast dissolution but followed by a gradual decrease in drug concentration, which suggests a slower phase transformation than DIF-PCL IC. These phase transformation were more clearly revealed by PXRD of the residual solids after different times intervals (Figure 4). Both DIF-PCL IC and DIF Form I transformed to a new solid form after 4 days in the phosphate-citrate buffer, and showed almost the same equilibrium solubility (1.036 ± 0.024 mg/mL and 1.027 ± 0.039 mg/mL, respectively). The transformation of DIF-PCL IC was much faster than that of DIF Form I, with all the IC crystals transformed to the new solid form within 4 h and the drug concentration approached to a plateau value. In contrast, partial transformation to the new solid form was observed for DIF Form I at the same time period


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(Figure 4), which was consistent with the gradual decrease in drug concentration on its dissolution profile. The solid form transformed from DIF-PCL IC and DIF Form I at pH 6.4 under non-sink conditions was thoroughly characterized with PXRD, DTA and TGA (Figure S3 and S4), and it seemed to be the monosodium bis-diflunisal salt monohydrate (DIF•DIF-Na+•H2O), which was previously mentioned in the literature25. After heated at 160 °C, the collected solid transformed to a mixture of DIF sodium salt and DIF Form I crystals (Figure S3), which was also confirmed by the separate decomposition temperatures of these two crystal forms in the DTA curves during heating (Figure S4). An obvious weight loss (~3.4 wt%) was observed for the collected solid in the temperature range of 110 ~ 126 °C in the TGA analysis (Figure S4), consistent with the theoretical water weight percentage of the assumed monosodium bis-diflunisal salt monohydrate (3.3 wt%). Therefore, it can be concluded that both DIF-PCL IC and DIF Form I transformed to the monosodium bis-diflunisal salt monohydrate crystals at pH 6.4 under non-sink conditions. For DIF-PCL IC system, the residual solid was a mixture of that salt hydrate crystal and PCL crystal.


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Figure 4. PXRD patterns of the residual solids collected from the pH 6.4 buffer after different time intervals under sink and non-sink conditions. Diffraction patterns of the raw materials are also given as a reference. The dashed lines indicate the characteristic peak locations of PCL crystal (blue) and the new salt hydrate crystal (red) formed during the dissolution process.


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Structure of the Dissolving Particles To further clarify the dissolution process, the residual particles of DIF-PCL IC being dissolved at pH 6.4 under sink conditions were removed from the suspension and observed under POM at different time intervals from the start of dissolution (Figure S5a). The partially dissolved IC particles showed an obvious core-shell structure, with the shell layer apparently also being crystalline. As time proceeded, the shell layer became thicker at the expense of the core until the core disappeared. When heated, these residual crystals completely melted at a temperature range from 55 to 60 °C (Figure S5b), suggesting they are pure PCL crystals, which is also consistent with the results of PXRD characterization (Figure 4). Similarly, the shells of the partially dissolved IC particles also melted at a temperature range from 50 to 60 °C, while the core part did not change (i.e., remaining as DIF-PCL IC crystals) (Figure S5c). Therefore, it can be concluded that the core-shell structure formed during dissolution of the DIF-PCL IC crystals is composed of an IC core and a crystalline PCL shell. In contrast to this dissolution behavior at pH 6.4, the IC particles at pH 4.4 exhibited a similar but much slower dissolution process under sink conditions, and only a small amount of crystalline PCL formed on the particle surface after 14 h, as evidenced by the weak birefringence at the peripheral part of the particle (Figure S6). The formation of core-shell structure during the dissolution was more clearly illustrated by continuous observation of a single IC particle at pH 6.4 (Figure 5). Similarly, the dissolution was initiated at the surface of the suspended IC particle, then gradually evolved into the interior, resulting in the in-situ formation of PCL-coated IC particles. Interestingly, the size and shape of the IC particles remained almost the same before and after dissolution. Since the PCL component constitutes only a small part of the initial IC crystals (~10 wt%), the recrystallized PCL shells and the post-drug-dissolution particles should be highly porous. The evolution of the


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morphology of DIF-PCL IC particles during dissolution was characterized by SEM (Figure 6). The IC particles exhibited a compact surface before dissolution, but cavities formed on the particle surface upon dissolution, and generated a highly porous structure after the complete dissolution of the IC crystals (pH 6.4, 4h).

Figure 5. In-situ POM observation of the dissolution process of a DIF-PCL IC particle at pH 6.4 under sink conditions. The dissolution was initiated at the peripheral part of the particle, leading to the formation of a core-shell structure during dissolution and finally a crystalline PCL particle.


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Figure 6. SEM images of the surface morphology of DIF-PCL IC particles as prepared and dissolved under sink conditions after different time intervals at pH 4.4 and pH 6.4. Under non-sink dissolution conditions at pH 6.4, the porous but crystalline PCL shells on the dissolving IC particles might act as the heterogeneous nucleation sites to accelerate the phase transformation to the sodium salt hydrate of DIF, thus explaining the faster concentration declines in the IC system than in the DIF Form I system (Figure 2b). This hypothesis was supported by the in-situ POM observation (Figure S7a): PCL shells formed on the particle surface upon dissolution, then followed shortly by the appearance of the fine needle-like salt hydrate crystals apparently initiated at the particle surface. However, DIF Form I showed a much slower phase transformation process under the same condition (Figure S7b), consistent with the gradual decrease in drug concentration during the dissolution of DIF Form I (Figure 2b). The formation mechanism of crystalline PCL shell layer from the initially isolated PCL chains in the DIF-PCL IC crystals is interesting and deserves more discussion. Outside the


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pharmaceutical field, urea-PCL and cyclodextrin-PCL IC solids were extensively studied by Tonelli et al26-29. Similarly, they also found that, after removal of the soluble urea and cyclodextrin, the PCL chains coalesced and crystallized. One unique property of such systems is that the extended and less-entangled nature of the polymer chains in their ICs were largely retained upon removal of the host lattice structure, leading to the formation of coalesced polymer chains with strong crystallization ability. Consequently, the recrystallized PCL would display substantially elevated melt-crystallization temperatures (Tc) and narrower exotherm compared with conventional PCL samples. We tested the melt crystallization behavior of the residual PCL solid and the results confirmed such profiles (Figure 7 and Table 1). Therefore, it is reasonable to conclude that the PCL crystals formed during DIF-PCL IC dissolution should also consist of coalesced PCL chains with extended conformations and less entanglement, as schematically shown in Figure 8.


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Figure 7. DSC cooling scans for the melt-crystallization behavior of the coalesced and raw PCL. The coalesced and raw PCL were heated to 80 °C at a heating rate of 10 °C/min, and kept at this temperature for 5 min. Afterwards, these PCL samples were cooled to 0 °C at a cooling rate of 20, 10 and 5 °C/min, respectively. The exotherm corresponding to the melt-crystallization of PCL was recorded during the cooling process. Table 1. Melt-crystallization temperatures (Tc) of the coalesced and raw PCL at different cooling rates. Tc (°C)

a

cooling rate (°C/min)

raw PCL

coalesced PCL

∆T (°C)a

5

34.4

40.8

6.4

10

28.5

38.4

9.9

20

26.0

35.1

9.1

∆T = Tc, coalesced - Tc, raw


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Figure 8. Proposed mechanism for the formation of porous PCL shells on the IC particles during dissolution through the coalescence of PCL chains. PCL chains residing in the IC channels are in the isolated and extended state. The dissolution of DIF framework facilitates the contact and hence aggregation between adjacent PCL chains. The extended and less-entangled nature of PCL chains in the IC crystals, as well as the volume of the initial IC particles, are largely retained in the coalesced samples, leading to the formation of highly porous PCL shells.


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Proposed Phase Solubility Diagram Combing all the aforementioned results and inspired by the co-crystal literature10-12,30,31, the dissolution behavior of DIF-PCL ICs can be schematically summarized in a phase solubility diagram (Figure 9). At pH 4.4, the stable species of DIF in the solid phase is the unionized free acid molecules, while in the solution phase both the unionized and ionized DIF species co-exist. Similar to the conventional co-crystals, the IC-solution equilibrium can be represented as the solubility product of the two crystal constituents (the SPIC curve in Figure 9)32. It should be noted that, though PCL is almost insoluble in water, its practical solubility is assumed not equal to zero so the IC solution equilibrium can be represented by the solubility product of the crystal constituents. At pH 4.4 under non-sink conditions, the dissolution of DIF-PCL IC evolves along the dissolution line, which is defined by the composition ratio of DIF and PCL in the inclusion complexes, possibly goes through the phase region marked with red stripes, and finally reaches the equilibrium state (Point A in Figure 9), which is the intersection between the SPIC curve and the PCL solubility line. At Point A, the equilibrium solid consists of IC crystals and PCL crystals. In contrast, at pH 6.4 under non-sink conditions, the dissolution of DIF-PCL IC reaches a different final equilibrium state (Point B in Figure 9), which is a mixture of the salt hydrate crystals and the coalesced PCL crystals.


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Figure 9. Proposed phase solubility. At pH 4.4 and pH 6.4 under non-sink conditions, the dissolution of DIF-PCL IC reaches the final equilibrium states labeled respectively with A and B. The black dashed lines represent the equilibrium solubility of DIF Form I, DIF salt hydrate and PCL under the corresponding conditions.

Conclusion In this study, DIF-PCL IC was used as a model system to demonstrate the effect of hydrophobic polymers on the dissolution behavior of drugs from their inclusion complex crystals. Different from our previous studies on the ICs formed with the soluble polymer PEG, the new system showed much richer behavior and generated interesting structures. As DIF is a weakly acidic drug, the dissolution profiles of DIF-PCL IC also exhibited a strong pH


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dependence. At pH 4.4, DIF-PCL IC crystals were stable and exhibited decreased drug solubility and dissolution rate compared with the pure DIF crystal, demonstrating the possibility of using drug-PCL inclusion complexes to slow down the drug dissolution. While at pH 6.4, the complex dissociated rapidly as DIF transformed into a salt hydrate crystal form. The structure evolution of the DIF-PCL IC crystals during the dissolution was studied in detail. The PCL chains initially reside isolated in the channels DIF-PCL IC. As the DIF molecules dissolve, the PCL chains coalesce and form crystalline but porous PCL shell layers on the particles. Probably because of its highly porous nature, this in-situ formed PCL shell layer does not seem to inhibit the dissolution of the drug molecules from the IC core. However, this core-shell structure represents a novel structure type in the pharmaceutical solid, and since PCL is biodegradable and also used in many biomedical products, this core-shell structure seems interesting and worth further studies.

ASSOCIATED CONTENT Supporting Information. Additional characterization results of DSC, PXRD, NMR, TGA, and POM were included in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author


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Corresponding authors: Jun Xu (email: [email protected]) and Yanbin Huang (email: [email protected]) Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. (match statement to author names with a symbol) ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (Grant No. 21374054 and No. 21434008).

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total concentration of DIF in solution is the sum of the ionized and unionized species, and is given by DIF = DIF + DIF Therefore, combining the above equations gives the apparent solubility product curve (SPIC) of DIF-PCL IC at a particular pH: ⁄

(1 + 10#$% ) DIF PCL⁄ =


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For Table of Contents used only

The Dissolution Behavior of the Crystalline Inclusion Complex Formed by Drug Diflunisal and Poly(ε-caprolactone) Zhi Zhong, Xiaotong Yang, Bao-hua Guo, Jun Xu*, and Yanbin Huang*

Drug-PCL inclusion complexes can slower the drug dissolution and generate porous PCL structures


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Dissolution Behavior of the Crystalline Inclusion Complex Formed by

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