Journal of Pharmaceutical and Biomedical Analysis 137 (2017) 42–53
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Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding Martina Cugovˇcan a , Jasna Jablan b , Jasmina Lovric´ c , Dominik Cinˇcic´ a , Nives Galic´ a , Mario Jug c,∗ a
University of Zagreb, Faculty of Science, Chemistry Department, Horvatovac 102A, Zagreb, Croatia University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Analytical Chemistry, A. Kovaˇci´ca 1, Zagreb, Croatia c University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Pharmaceutical Technology, A. Kovaˇci´ca 1, Zagreb, Croatia b
a r t i c l e
i n f o
Article history: Received 23 November 2016 Received in revised form 9 January 2017 Accepted 9 January 2017 Available online 10 January 2017 Chemical compounds studied in this article: Praziquantel (PubChem CID: 4891) -cyclodextrin (PubChem CID: 444041) Hydroxypropyl--cyclodextrin (PubChem CID: 44134771) Methyl--cyclodextrin (PubChem CID: 51051622) Sulphobutylether--cyclodextrin sodium salt (PubChem CID: 71307541) Citric acid (PubChem CID: 311) Mailc acid (PubChem CID: 525) Salicylic acid (PubChem CID: 338) Tartaric acid (PubChem CID: 444305)
a b s t r a c t Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl--cyclodextrin (HPCD) and randomly methylated -cyclodextrin (MECD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (Papp (PZQ) = (3.72 ± 0.33) × 10−5 cm s−1 and Papp (PZQ/HPCD) = (3.65 ± 0.21) × 10−5 cm s−1 ; p > 0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug. © 2017 Elsevier B.V. All rights reserved.
Keywords: Praziquantel Grinding Cocrystal Cyclodextrin complex Chemical stability Dissolution In vitro permeability
1. Introduction Praziquantel (PZQ) is an anthelmintic drug effective against a broad range of trematodes and cestodes as well as the drug of choice for therapy and prevention of schistosomiasis. According to the World Health Organization, there are close to 240 million peo-
∗ Corresponding author at: Department of Pharmaceutical Technology, Faculty ´ 1, 10 000 Zagreb, of Pharmacy and Biochemistry, University of Zagreb, A. Kovaˇcica Croatia. E-mail address:
[email protected] (M. Jug). http://dx.doi.org/10.1016/j.jpba.2017.01.025 0731-7085/© 2017 Elsevier B.V. All rights reserved.
ple infected by this acute and chronical parasitic disease, mainly in poorly developed tropical and subtropical areas of Africa and Asia [1,2]. PZQ is low-cost drug with a good safety and acceptable therapeutical profile. Beside the human medicine, it is widely used in veterinary medicine too [3]. The drug is administered as a racemate, where R-enantiomer is eutomer, while S-enantiomer is associated with side effects and is primarily responsible for extremely bitter taste of the drug [4]. Interestingly, it has been reported that PZQ can enhance the humoral and cellular immune response of the body against the parasite [5]. Furthermore, some preclinical investigations have shown that PZQ could greatly enhance the anticancer activity of paclitaxel in various cell lines [6] and it shows inhibitory
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effect on P-glycoprotein [7]. Therefore, it might be reasonably presumed that the therapeutic indications of PZQ might be extended in the future. However, PZQ has limited aqueous solubility of 0.04 mg/mL and is classified as type II drug according to the Biopharmaceutical Classification System, indicating that its efficiency is markedly affected by the dissolution process [8]. After absorption the drug undergoes an extensive first pass metabolism. In addition, considerable inter-individual variation for unknown reasons in the drug absorption and clearance rate have been observed [3]. All this is limiting the therapeutic efficiency of the drug. Several strategies aimed to increase PZQ limited solubility have been reported in the literature, including cyclodextrin complexation [9–13], formulation of solid dispersions with povidone [14], poloxamer 188 [15], hydrogenated castrol oil [16] or incorporation into liposomes [17]. However, those systems were manly prepared using large quantities of the organic solvents, which can be harmful to the environment and hazardous for the patients’ health, thus requiring complicated and expensive technologies for complete solvent removal form the formulation as well as expensive waste management [18]. Different prolonged release formulations of PZQ aimed for parenteral administration in veterinary medicine were also described, including poly(-caprolactone) implants [19], PLGA and solid lipid nanoparticles [20,21]. However, the drug release from such controlled delivery systems is slow and incomplete, clearly underlying the need for improving the PZQ physicochemical and biopharmaceutical properties by an adequate technology. In the past decades mechanochemical activation by grinding appeared as rapid, highly effective, solvent-free and sustainable green chemistry approach suitable to prepare different systems based on covalent, coordination and non-covalent bonds [22–25]. Furthermore, cocrystallization by grinding has become a proven and accepted way of modifying physical and chemical properties, such as colour [26,27], hygroscopicity [28,29], thermal stability and solubility of solid materials [30,31]. The mechanical energy supplied to the drug material by grinding in the high energy vibrational mills first leads to the particle size reduction up to some critical threshold, followed by drug amorphization. Further energy supply to the system results in its mechanical activation making it prone to the chemical reaction in the solid state. However, such activated co-ground products are usually far from being stable, at least from the pharmaceutical point of view, requiring the addition of at least one or more component to the grinding mixture which would stabilise the activated drug form, yielding in pharmaceutically stable product. This technique is known as neat grinding (NG), [23,32–34]. In some cases, the addition of small (catalytic) amounts of solvent is required, in order to induce the interaction between the drug and additive during the grinding procedure, resulting in a higher yield of the product with the desired properties. Such technique is known as liquid assisted grinding (LAG), [35–37]. Both grinding techniques are highly versatile, allowing the preparation of different products, depending on the type of the additive used [22,23,38]. PZQ does not contain salt-forming groups in its chemical structure and therefore, a salt formation as an approach to increase its solubility cannot be used. Taking that into account, the aim of this work was to prepare its cocrystals and cyclodextrin complexes by mechanochemical activation. This, however, requires a precise regulation of different process and formulation variables, including the grinding time, additive type and drug to additive ratio in order to successfully prepare a desired product. With this intention, the drug was subjected to the grinding in the presence of diverse additives, including different organic acids and several cyclodextrin derivatives, as well as their combinations. Citric (CA), malic (MA), salicylic (SA) and tartaric acids (TA) contain several carboxylic and hydroxyl groups in their structure and have been recognised as suitable coformers of the cocrystals, able to interact with the
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complimentary functional groups of the drug molecule by the hydrogen bonding [39]. Furthermore, SA is recognised as an intestinal permeation enhancer [40], which could also enhance the in situ drug absorption into tapeworms present in the intestinal lumen. Although PZQ co-crystals with some of those organic acids are already reported [41,42], their pharmaceutical potential was not systematically evaluated. The list of cyclodextrin used included parent -cyclodextrin (CD) and its hydroxypropyl (HPCD), methyl (MECD) and sulphobuthylether (SBECD) derivatives. A detailed characterization of the prepared products by the solid state analysis was performed and their physiochemical and biopharmaceutical properties were determined, in order to select products suitable for the development of advanced drug delivery systems of PZQ. 2. Materials and methods 2.1. Materials (±) Praziquantel (PZQ) was kindly supplied by Genera d. d. (Croatia). Co-grinding additives used in this study were -cyclodextrin (CD, Cawamax W7 Pharma), hydroxypropyl-cyclodextrin (HPCD, Cavasol W7 HP Pharma, with an average degree of substitution of 0.9) and randomly methyl--cyclodextrin (MECD, Cavasol W7 M Pharma, with an average degree of substitution of 1.8) which were all obtained from Wacker Chemie GMBH (Germany). Sulphobutylether--cyclodextrin sodium salt with a substitution degree of 0.9 (SBE--CD, Captisol) was obtained from CyDex Inc (USA). Organic acids used were salicylic acid (SAL), citric acid monohydrate (CA), DL-malic acid (MA) and L-(+)-tartaric acid (TA), all obtained by Sigma-Aldrich (USA). Simulated gastric fluid pH 1.2, simulated duodenal fluid pH 4.5 and simulated intestinal fluid pH 6.8, all without enzymes, were prepared according to the monograph 5.17.1 of the European Pharmacopeia (8th ed.). 2.2. Preparation of the co-ground PZQ binary and ternary samples Solid binary and ternary products of PZQ with different additives were prepared by co-grinding their corresponding equimolar mixtures in a high-energy vibrational micromill (Mixer Mill MM 200, Retch, GmbH, Germany) at an ambient temperature. Cocrystals with selected acids were prepared by both neat grinding and liquid assisted grinding. 150 mg of PZQ and an equimolar amount of selected organic acid were accurately weighted, transferred into 10 mL volume stainless steel grinding jars containing two 7 mm stainless steel grinding balls and subjected to neat grinding at 25 Hz over 30 min, with or without an addition of 15 L of absolute ethanol. Binary PZQ complexes with cyclodextrins and ternary complexes with selected cyclodextrins and organic acid were prepared by neat grinding at 25 Hz for 30 min in an equimolar drug to additive ratio. In all cases, the batch size was 200 mg. To evaluate the effect of the applied procedure on the PZQ solid state properties, the drug alone was also submitted to the grinding under the same conditions. The obtained products were stored in a desiccator at room temperature. Physical mixtures were prepared by gently blending PZQ and the selected additive at the given ratio in a mortar with spatula immediately before the use. 2.3. Differential scanning calorimetry (DSC) DSC analysis was performed with a Perkin-Elmer DSC 7 instrument (PerkinElmer, Inc., USA) calibrated with indium (99.98% purity; melting point 156.61 ◦ C and fusion enthalpy of 28.71 Jg−1 ) prior the analysis of the sample under nitrogen purge (25 mL/min). Accurately weighted samples (2–5 mg, Mettler M3 Microbalance) were placed in sealed aluminium pans with pierced lid and scanned at a heating rate of 10 ◦ C min−1 over the temperature range of
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25–200 ◦ C. The relative degree of drug crystallinity (RDC) in the samples was calculated according to Eq. (1) RDC =
Hsample Hdrug
× 100%
(1)
Dissolution efficiency after 60 min (DE60min ), defined as the area under the dissolution curve up to 60 min, expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time [43], was calculated according to the following equation:
t 0
Qdt
where Hsample and Hdrug are the fusion enthalpies of the PZQ in the product (normalised to the drug content) and in the pure drug, respectively. Measurements were carried out in triplicate and the relative standard deviation of crystallinity data was 0.05). Standard deviation values were omitted for clarity. In all cases, the relative standard deviation was below 1%.
The quantitative determination of PZQ was performed using ® an Agilent 1290 Infinity II LC System equipped with LiChrospher ® 100 RP-18 (5 m) LiChroCART 250-4 column (Merck Milipore, Germany) thermostated at 25 ◦ C. The mobile phase consisted of acetonitrile/water (45:55, v/v), the flow rate was 1 mL/min with an injection volume 20 L for solubility, in vitro dissolution and stability testing. For the Caco-2 cell monolayer permeability study the injection volume was increased to 100 L. The column eluent was monitored at 210 nm resulting in PZQ retention time of about 9 min.
*
2.10. HPLC assay of praziquantel
– – 1:1 molar ratio
where ∂Q/∂t is the permeation rate, A is the diffusion area of the monolayer and c0 is the initial concentration of PZQ in the upper compartment [44].
– – citric acid malic acid salicylic acid tartaric acid -cyclodextrin hydroxypropyl--cyclodextrin randomly methylated--cyclodextrin sulphobuthylether--cyclodextrin hydroxypropyl--cyclodextrin and malic acid randomly methylated--cyclodextrin and malic acid
(3)
PZQ PZQ GR PZQ/CA PZQ/MA PZQ/SA PZQ/TA PZQ/CD PZQ/HPCD PZQ/MECD PZQ/SBECD PZQ/HPCD/MA PZQ/MECD/MA
∂Q 1 × A × c0 ∂t
Drug to additive ratio
Papp =
Co-grinding additive
2.9.3. Caco-2 cell monolayer permeability study Caco-2 cells were seeded onto the polycarbonate 12-well ® Transwell inserts (0.4 m pore size, 12 mm diameter, surface area 1.12 cm2 , Corning B.V. Life Sciences, Amsterdam, The Netherlands) at a density of 2.5 × 104 cells/well and the confluent monolayers (20–22 days) were used for permeability studies. Cells were cultured with frequent medium changes (every other day for the first 10 days and every day thereafter). The transepithelial electrical resistance (TEER) of the monolayer was measured using STX-2 electrode and voltohmmeter EVOM (WPI Inc., Sarasota, Florida, USA) to determine the formation of the monolayer and its integrity during the experiment. Permeability studies were carried out in HBSS. Test samples were prepared by diluting stock solution of PZQ and selected co-ground system with HBSS up to a 0.1 mM PZQ concentration. Prior to the experiment, the monolayers were washed with HBSS, after which HBSS was placed into the upper (400 L) and lower compartments (1200 L). The cells were then incubated for 30 min. At the start of the experiment, the upper compartment was emptied and 400 L of the test sample was added. Samples (400 L) were taken from the lower compartment at regular time intervals over 120 min and replaced with the same volume of fresh buffer. At the end of the experiment, the 300 L of the solution remaining in the upper compartment was also collected. All experiments were conducted in triplicate at pH 7.4, 37 ◦ C, 5% CO2 and 95% relative humidity. Samples were diluted with acetonitrile to obtain a water-toacetonitrile volume ratio of 45:55 and then analysed for PZQ content using HPLC. Apparent permeability coefficients (Papp ) were calculated according to the following equation:
45
Sample
isopropanol (Kemig, Croatia). The absorbance was measured at 570 nm by using microplate reader (1420 Multilabel counter VICTOR3, Perkin Elmer, Waltham, Massachusetts, USA). Mitochondrial activity was expressed relative to a control group incubated with HBSS only.
Table 1 Composition of the prepared co-ground systems of PZQ and their physiochemical characteristics: PZQ melting point (Tonset ), fusion enthalpy (Hfuz ), relative crystallinity (RDC) and solubility in simulated gastric fluid pH 1.2, simulated duodenal fluid pH 4.5 and simulated intestinal fluid pH 6.8 (s0 ).
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3. Results and discussion
lying the need for suitable co-grinding additive in order to improve the solubility of the drug.
3.1. Effect of grinding on the solid state properties of PZQ 3.2. Cocrystals Mechanochemistry has been recognised as a leading green technology for production of solid dispersions and innovative supramolecular systems such as cocrystals or inclusion complexes [18,45–47]. The first step in development of such products is to evaluate the effect of grinding procedure on the physiochemical properties of the drug. With this instance, PZQ was subjected to the neat grinding and analysed by XRPD, DSC and FTIR analysis. The effect of the grinding on the drug solubility was also monitored (Table 1). XRPD analysis (Fig. 1) revealed crystalline nature of the drug, presenting two double scattering peaks in 6.7-8.5◦ 2 values, high intensity peaks at 4.01◦ , 15.42◦ , 16.74◦ and 20.09◦ , as well as several secondary peaks, confirming the presence of racemic mixture of PZQ in the sample [48,49]. DSC trace of pure PZQ (Figure A.1) showed an endothermic fusion peak with onset temperature and fusion enthalpy values (Table 1) also characteristic for the PZQ racemate [48]. In the PZQ sample ground for 30 min, the XRPD pattern did not differ significantly compared to that of pure compound (data not shown). However, the fusion peak in the DSC thermogram of ground PZQ appeared at somewhat lower temperature and with a reduced fusion enthalpy (Table 1) indicating partial reduction of the sample crystallinity for 19% with respect to that of untreated PZQ. For structural characterization of the potential changes caused by the grinding procedure, the FTIR spectra of PZQ samples were acquired in both transmittance and attenuated total reflection (ATR) mode. As can be seen from Fig. A2 , the grinding did not influence the PZQ structure, and the corresponding IR spectra are the same for both treated and untreated compound. The solubility of the drug was not changed substantially after the grinding procedure. The untreated PZQ as well as the ground compound appeared to be only slightly soluble in the pH-range studied and the changes of its solubility in the media with different pH values were not statistically significant (p < 0.05; Table 1), clearly under-
To prepare cocrystals of PZQ with selected organic acids, two different preparation techniques were applied. The first one was NG of the compounds in an equimolar ratio, while other was LAG where small (catalytic) amounts of ethanol as a solvent were added to equimolar drug/organic acid mixture in order to facilitate the cocrystals formation. XRPD analysis of the products obtained (Fig. 1) showed that NG resulted in products with reduced crystallinity where peaks typical of starting components still could be observed. LAG on the other hand was more efficient in the preparation of PZQ cocrystals with selected organic acids. When CA was used as a cocrystal former, LAG resulted in a pasteous product. It seems that addition of small amount of ethanol caused the liberation of crystalline water present in citric acid during the cogrounding process. In all other cases, products obtained by both NG and LAG were free-flowing powders. In the XRPD pattern of PZQ/CA product prepared by LAG, several new peaks at 18.51, 22.74 and 25.65 2◦ values were observed, indicating the formation of a new cocrystal (Fig. 1A). In the DSC thermogram of PZQ/CA prepared by LAG, a new endothermic peak with an onset temperature of 51.07 ◦ C (H = 17.2813 J/g) could be observed (Fig. A3A), confirming the formation of the new solid phase. Such peak was not present in the thermogram of the PZQ/CA sample prepared by NG. In both thermograms, peaks corresponding to the melting of the starting compounds, clearly visible in case of plain physical mixture, were not observed. The XRPD pattern of PZQ/MA prepared by LAG showed several new peaks at 7.11, 8.82, 9.48, 13.74, 19.68, 20.46 and 22.98 2◦ values (Fig. 1). For PZQ/TA and PZQ/SA prepared by the same method, new peaks were observed at 7.20, 8.82, 9.48, 13.74, 19.68, 20.46, 21.81, 22.98 and 7.20, 8.99, 9.72, 18.39, 19.32, 21.81 2◦ values, respectively. Furthermore, the comparison of the XRPD patterns of
Fig. 1. XRPD patterns of PZQ, selected organic acids and their equimolar co-ground products with citric acid (CA; A), malic acid (MA; B), salicylic acid (SA; C) and tartaric acid (TA; D) prepared both by neat grinding (NG) and liquid assisted grinding (LAG).
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Fig. 2. FTIR-ATR spectra of untreated drug, organic acids and corresponding binary products prepared by LAG: PZQ (1), MA (2), PZQ/MA (3), SA (4), PZQ/SA (5), CA (6), PZQ/CA (7), TA (8), PZQ/TA (9).
PZQ, the respective organic acids and the solids obtained revealed that the products prepared by LAG do not contain peaks of residual starting materials, suggesting the cocrystal formation in 1:1 stoichiometric ratio [41]. The DSC analysis also confirmed new solid phase formation in case of PZQ/TA sample prepared by LAG. In the DSC thermogram the sample presented a new peak at 150.81 ◦ C with the fusion enthalpy of 80.98 J/g, substantially different from that of the starting material (Fig. A3D), while in the sample prepared by NG a peak at 105.75 ◦ C was observed, probably corresponding to some thermally induced interaction of the staring materials brought by NG. DSC was of little value in characterization of the PZQ/MA and PZQ/SA samples due to thermally induced interaction between the components during the thermal treatment, observed by the analysis of the corresponding physical mixtures (Figs. A3B and A3C). Further information about the cocrystal formation was obtained by FTIR analysis of the samples prepared (Fig. 2). The amide I bands, which mainly involve the carbonyl stretching vibrations of the amide group, characteristic for two C O groups in PZQ were recorded at 1649 and 1628 cm−1 [41]. The later one can be assigned to more rigid carbonyl group at the piperazinone ring. By inspecting the ATR spectra presented in Fig. 2, it can be easily observed that those two bands were shifted to lower wavenumbers in spectra 3, 5 and 9 (to 1612, 1593 and 1606 cm−1 , respectively), indicating that new solid phases upon LAG of PZQ with carboxylic acids, MA, SA and TA were formed. The formation of hydrogen bonds between PZQ and cocrystal former resulted in lowering the energy required for stretching of the C O bonds. Since both of the bands in spectrum of PZQ are shifted, and only one broader band is noticeable in spectra 3, 5 and 9 (Fig. 2), it is reasonable to assume that both carbonyl groups are involved in H–bond formation. In addition, the shift of band from 1653 to 1670 cm−1 , assigned to C O stretching vibrations of salicylic acid (Fig. 2, spectra 4 and 5), confirms
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the formation of new H–bonds and embedding of carboxylic acid in the cocrystal [41]. In ATR spectrum of MA the strong band at 3438 cm−1 was assigned to (OH) of CHOH group, the broad one around 3000 cm−1 to (OH) of COOH hydrogen bond mode and the broad one in region 2600–2500 cm−1 to hydrogen bond mode in dimer. Three bands at 1737, 1714 and 1683 cm−1 ware assigned to (C O) of dimeric COOH group [50]. By comparing the IR spectra of pure MA and its mixture with PZQ (Fig. 3, spectra 2 and 3) considerable difference in band intensities at 3438 cm−1 and 1683 cm−1 , characteristic for OH and C O can be noticed, indicating that the hydroxyl group from CHOH group of MA, also, and probably dominantly participate in H–bond formation with PZQ carbonyl groups. The bands at 3402 and 3330 cm−1 in spectrum 8 were assigned to (OH) stretching of alcoholic group in TA, and the ones at 3100 cm−1 to (OH) stretching in carboxylic groups. The shift of bands and the appearance of one new around 3480 cm−1 in spectrum 9 indicate the H-bond formation between alcoholic groups of TA with PTQ. The stretching of two carbonyl groups in COOH was recorded at 1733 and 1716 cm−1 [51]. In the IR spectrum of the complex (Fig. 2, spectrum 9), only one band was observed at 1732 cm−1 . Although no shift of bands characteristic for PZQ was detected in spectrum 7, the shift of C O group of CA [52] from 1751, 1745 and 1699 cm−1 to 1753, 1726 and 1691 cm−1 can suggest the formation of new solid form. It should be emphasis that in all studied systems no new solid phases were obtained just by plain mixing of starting components in agate mortar or neat grinding. The spectra of resulting mixtures prepared in that way correspond to the sum of spectra of individual components (Fig. A4). The prepared cocrystals showed pH-dependent solubility (Table 1). The highest saturation solubility was observed at pH 4.5. The organic acids used contain several ionizable groups in their structure. The corresponding pKa values for CA are 3.13, 4.76 and 6.40; for MA 3.40 and 5.13; for TA; 2.98 and 4.34 [53], while for SA pKa valus are 2.97 and 13.74 [54]. At pH 1.2, when organic acids are completely unionized, the saturation solubility of the cocrystal formed is the lowest (Table 1). The increase of pH value to 4.5 leads to ionization of carboxyl group in the molecule of organic acid, thus contributing to the product solubility. Further ionization with the increase of the pH decreases the interaction between dissolved drug and the charged organic acid and lead to decrease in product solubility. Among the tested samples, PZQ cocrystals prepared with malic acid showed the highest solubility, thus they were considered for further phase of the product development. 3.2.1. Cyclodextrin complexes To prepare cyclodextrin complexes of PZQ, NG procedure was used. The XRPD analysis showed that efficiency of interaction was inversly related the crystallinity of the cyclodextrin derivative used. -cyclodextrin, as a crystalline compounds was the least effective, resulting in products where peaks corresponding to the both starting materials still could be observed (Fig. 3A). DSC analysis of this sample also revealed high level of residual drug crystallinity (Table 1), clearly indicating the inability of neat grinding procedure to promote solid-state interactions between the components, probably due to high crystal lattice stability of the -cyclodextrin. Efficiency of liquid assisted grinding in induction of the solidstate interaction between PZQ and CD was comparable (data not shown). As a consequence, the increase of the PZQ solubility in such product was only 88% higher than that of the pure drug (Table 1.). The NG of PZQ with amorphous cyclodextrin derivatives (HPCD, MECD and SBECD) resulted in amorphous products, as confirmed by both XRPD and DSC analysis (Figs. 3 and A.5). Such result is in agreement with previous research, clearly showing the superior affinity of the amorphous cyclodextrin derivatives for the solid-state interactions with drug promoted by NG [55,56]. Furthermore, those amorphous cyclodextrin derivatives contains
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Fig. 3. XRPD patterns of PZQ, selected cyclodextrins and their equimolar co-ground products with -cyclodextrin (CD; A), hydroxypropyl--cyclodextrin (HPCD; B), randomly methlyted--cyclodextrin (MECD; C) and sulphobuthyl--cyclodextrin (SBECD; D) prepared by NG.
up to 5% of the absorbed moisture, whose liberation during the mechanochemical treatment could contribute to the interaction between the compounds treated. The use of cyclodextrins as additives in the grinding procedure was the most efficient in increasing the PZQ saturation solubility. Compared to that of pure drug, an increase ranging from 110% (PZQ/SBECD) up to 137% (PZQ/MECD) was observed (Table 1). Previous NMR investigation showed that when such amorphous products are exposed to water, they are readily converted to inclusion complexes, increasing significantly the aqueous solubility of the drug in question [55]. In order to exploit the beneficial influence of MA on the PZQ solubility and to investigate potential synergic effect between MA and HPCD or MECD, 1:1:1 equimolar products were also prepared by the NG procedure. As shown by XRPD and DSC analysis (Figs. 3B, C, S5B and A.5C), ternary co-ground products with MA and both cyclodextrin derivatives were amorphous products. However, their saturation solubility was lower than that of the corresponding cocrystal or binary cyclodextrin compounds (Table 1). Therefore, in order to fully evaluate their biopharmaceutical potential and exclude the problems related to the supersaturation phenomena, in vitro dissolution studies were performed.
3.3. In vitro dissolution studies The in vitro dissolution studies of the selected samples were performed in simulated gastric (pH 1.2) and intestinal (pH 6.8) media without enzymes in order further evaluate the effect of cogrounding additives used on the dissolution rate of the products obtained (Fig. 4). The percentage of the dissolved drug at 15 min (Q15min ) was used as an indicator of the drug dissolution rate, while dissolution efficiency after 60 min (DE60min ) was taken as an index of the extent of the dissolution process [57] and are summarized in Table 2. As it can be observed from the presented data, the dissolution process of the pure drug is slow and incomplete in the studied time range, contributing to its low oral bioavailability [8]. All co-ground
products presented significantly superior dissolution properties compared to that of pure drug (p > 0.05; Table 2.) and the extent of the improvement observed was related to the type of the cogrinding additive used and the type of the system prepared. PZQ cocrystals with MA were the least efficient in increasing the drug dissolution properties (Table 2.). This can probably be related to the strength of newly formed crystal structure, stabilised by hydrogen bonds as discussed previously. In general, thermodynamic stability of the crystal lattice and solubility, as well as the corresponding dissolution rate of cocrystals formed are inversely related [54]. Amorphous cyclodextrin complexes, both binary and ternary, were more efficient in increasing the PZQ solubility when compared to cocrystal with MA (Table 2). This result can be related to the in situ inclusion complex formation when such amorphous co-ground product came in contact with the dissolution media, as discussed previously. Among cyclodextrin tested, product prepared with anionic SBECD was the least effective, while other showed comparable efficiency in increasing the dissolution rate of the drug, presenting DE60 min values near to 100% (Table 2). Because of the very low pKa of the sulfonic acid groups, SBECD carries multiple negative charges at physiological pH values [58], decreasing its affinity for in situ inclusion complex formation with lipophilic PZQ, thus reducing the solubility as well as the dissolution rate of the product formed (Tables 1 and 2). Interestingly, such product also demonstrated pH dependent dissolution rate (Table 2), which was not expected, taking into account that the saturation solubility of PZQ/SBECD co-ground complex did not change significantly in the tested pH range (Table 1). Furthermore, the dissolution properties for both ternary PZQ co-ground products were comparable to that of the corresponding binary complexes. The dissolution parameters obtained for both binary and ternary complexes were not statistically different (p > 0.05, Table 2), which is in contrast with the solubility data, where ternary complexes showed lower solubility than binary ones (Table 1.). Dissolution of both binary and ternary cyclodextrin complexes could lead to the formation of the supersaturated solutions [59]. The chemical potential of dissolved drug
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Fig. 4. In vitro dissolution profiles of selected co-ground samples in simulated gastric (pH 1.2) and simulated intestinal (pH 6.8) fluid at 37 ◦ C. For the sample codes please see Table 1.
Table 2 Percentage of dissolved drug at 15 min (Q15min ) and the dissolution efficiency at 60 min (DE 60min ) of selected co-ground samples in simulated gastric (pH 1.2) and intestinal (pH 6.8) media at 37 ◦ C. Sample
PZQ PZQ/MA PZQ/HPCD PZQ/MECD PZQ/SBECD PZQ/HPCD/MA PZQ/MECD/MA
pH 1.2
pH 6.8
Q15min /%
DE60min /%
Q15min /%
DE60min /%
9.89 ± 0.71 24.63 ± 3.06 95.09 ± 2.23 93.52 ± 0.39 51.80 ± 3.61 94.61 ± 1.91 96.44 ± 1.45
15.49 ± 2.47 29.35 ± 4.10 92.18 ± 1.09 92.48 ± 0.45 56.93 ± 3.11 92.97 ± 1.77 90.26 ± 1.59
9.86 ± 0.58 37.65 ± 3.02 97.78 ± 1.88 95.15 ± 0.45 67.00 ± 1.52 95.57 ± 2.89 98.81 ± 1.33
15.62 ± 2.39 42.42 ± 3.13 93.22 ± 0.74 91.11 ± 0.11 68.97 ± 1.67 95.11 ± 0.55 92.16 ± 1.35
molecules in such systems is high and it tends to stabilise through drug crystallization, resulting in decrease of dissolved drug concentration over time. It seems that PZQ ternary complexes are less effective in stabilizing the supersaturated drug solution formed after its dissolution when compared to that of the binary ones. A detailed analysis of this phenomenon would take part in our upcoming studies. 3.4. Chemical stability studies Co-ground binary complexes of PZQ with HPCD and MECD, as the products with optimal dissolution properties as well as MA cocrystal and the corresponding ternary complexes were subjected
to accelerated stability and photostability testing. The aim was to evaluate the influence of the used co-grinding additives to the chemical stability of PZQ in the samples prepared. The obtained results are presented in Fig. 5. Accelerated stability testing showed that PZQ degradation in selected samples followed pseudo-first order kinetic, with r2 value ranging from 0.918 to 0.986. In case of pure PZQ, the slope of the line obtained was not significantly different from zero (p > 0.05), indicating its stability and lack of PZQ degradation at 40 ± 2 ◦ C/75 ± 5% RH during 90 days (Fig. 6A.). In case of all coground samples tested, significant PZQ degradation was observed. The corresponding pseudo-first order degradation rate constants for PZQ/MA, PZQ/HPCD, PZQ/MECD, PZQ/HPCD/MA and
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Fig. 5. Changes in PZQ concentration in the selected co-ground samples during the accelerated stability studies at 40 ± 2 ◦ C/75 ± 5% RH (A) and photostability testing (B).
Fig. 6. Influence of PZQ, HPCD and co-ground PZQ/HPCD complex on the viability of Caco-2 cells determined by MTT assay (A). In vitro permeation profile of PZQ from tested samples at concentration of 0.1 mM across the Caco-2 cell monolayer (B).
PZQ/MECD/MA co-ground products were (2.75 ± 0.83) × 10−5 , (2.83 ± 0.74) × 10−5 , (3.33 ± 0.73) × 10−5 , (16.40 ± 2.85) × 10−5 and (17.23 ± 1.63) × 10−5 h−1 , respectively. Furthermore, analysed samples presented different levels of photodegradation (Fig. 5B). Again, the pure drug was the most stable, showing the statistically insignificant levels of photodegradation (p > 0.05). Similar result was also observed in case of co-ground PZQ/HPCD sample, while other products showed statistically significant photodegradation (p < 0.05). The most prominent photodegradation was observed for PZQ/MA cocrystals, resulting in degradation of approximately 7.9% of the drug dose. Other samples showed comparable levels of photodegradation, ranging from 4.3% in case of PZQ/MECD complex up to 6.8% for PZQ/HPCD/MA ternary complex (Fig. 6B). The observed results, especially in case of cyclodextrin based formulations, were rather surprising taking into account that the vast majority of publications are demonstrating the beneficial effect of cyclodextrin on chemical stability as well as photostability of different molecules [60–65]. The effect of cyclodextrin on the drug stability could be related to the inclusion mode of the drug into the central cavity of the cyclodextrin molecule. If the reactive group of the drug is shielded in the central cavity of cyclodextrin, the decrease in drug degradation will be observed. However, if such functional group is located outside the cyclodextrin cavity, the protective effect of cyclodextrin on the drug will be absent. Furthermore, the interaction of drug reactive functional groups and substituents on the cyclodextrin core could lead to destabilization of the drug molecule, catalysing its degradation [66]. This seems to
occur in case of co-ground products prepared. The complexation of PZQ with CD occurs by deep inclusion of the aromatic part of PZQ isoquinoline ring into the beta cyclodextrin cavity through the wider rim of the macrocycle [10]. Available data about PZQ thermal and photochemical degradation pathways showed that this took part at the pyrazino-4-one moiety of the drug [67,68], which is not shielded by the cyclodextrin complexation [10]. The differences in stability observed for HPCD and MECD co-ground products could be attributed to the higher affinity of the activated drug molecule for the interaction with more lipophilic methyl group, resulting in more pronounced catalytic effect of MECD on the PZQ degradation. The interaction of MA with PZQ in the corresponding cocrystal also seems to destabilize the drug molecule, making it especially prone to the photodegradation (Fig. 6B). Finally, MA and both cyclodextrins seem to have synergistic action on the PZQ destabilization, resulting in pronounced degradation of the corresponding ternary co-ground complexes (Fig. 6A). Therefore, they are not suitable for pharmaceutical application. Based on the result of the stability studies as well as taking into account its desirable dissolution properties, PZQ/HPCD co-ground complex was selected as the most prominent candidate for the further product development. 3.5. Biocompatibility and in vitro permeability studies Most cyclodextrins of current pharmaceutical interest are poorly absorbed from gastrointestinal tract with oral
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bioavailability generally below 4%, contributing to the lack of their systemic toxicity. This effect is related to cyclodextrin digestion by intestinal microflora, their high molecular weight ranging from 973 to 2163 kDa, large number of hydrogen donors and acceptors in their structure and high hydrophilicity with logKo/w between −8 and −12 [66]. However, cyclodextrins can interact with components of intestinal epithelial cell membrane, extracting lipids and cholesterol. This could lead to increased drug permeability but also to the local tissue irritation and damage [69–71]. Since a product biocompatibility is a key feature that has to be fulfilled, the effect of both starting components and co-ground PZQ/HPCD complex on the Caco-2 cell viability was analysed by MTT assay. The results are presented in Fig. 6A. In general, the treatment of Caco-2 cells with the PZQ, HPCD or their co-ground complex in the concentration range of 0.1–0.5 mM did not decrease significantly the cell viability (p > 0.05), indicating their biocompatibility. In fact, in the presence of HPCD and co-ground complex at concentration 0.1 and 0.3 mM and PZQ at 0.3 mM concentration an increase of the cell viability was observed, but this effect was not statically significant when compared to that of untreated cells (p > 0.05). The effect of DMSO, used in concentration ranging from 0.1 to 0.5% (v/v) to dissolve poorly soluble PZQ, was also monitored, but it did not present any statistically significant influence on the cell viability (data not shown), which is in agreement with literature data [72]. Permeability coefficients across monolayers of the human colon carcinoma cell line Caco-2, cultured on permeable supports, are commonly used to predict the absorption of orally administered drugs and other xenobiotics. Furthermore, this model could also be used to elucidate drug transport mechanisms and to estimate the effect of different carriers on the drug permeation process [73]. With this intention, the possible effect of tested samples on tight junction opening was investigated by monitoring the TEER of the Caco-2 monolayer during the exposure to the tested substances. The permeability profiles of PZQ across the Caco-2 cell monolayer are presented in Fig. 6B . The apparent permeability coefficient (Papp ) of pure PZQ was calculated to be (3.72 ± 0.33) × 10−5 cm s−1 , confirming that PZQ is highly permeable drug. The observed value is in good agreement with previously reported value [8]. The slightly higher value of PZQ Papp obtained by Dinora et al. (4.4 × 10−5 cm s−1 ), could be explained by the fact that they used ethanol to dissolve the drug. Ethanol is demonstrated to contribute to the drug permeation across Caco-2 cell monolayers [74]. In case of PZQ/HPCD co-ground complex, no significant difference in Papp of PZQ in comparison to the pure drug was observed ((3.65 ± 0.21) × 10−5 cm s−1 ; p > 0.05, Fig. 6B). This result is in agreement with previous data showing that thalidomide complexation with HPCD did not impair its intestinal permeability [75]. Furthermore, the observed TEER values during the permeability assay did not differ significantly compared to the untreated cell monolayers (data not shown), demonstrating that HPCD in tested concentration range did not lead to the opening of tight junctions in Caco-2 monolayer. Therefore, in order to permeate, the drug must dissociate from the complex. In this instance, the stability constant of the complex formed is of great importance. If the complex formed is of high stability, a decrease in drug permeation coefficient will be observed [76]. However, at a moderate values of the complex stability constant of 642 M−1 , determined for PZQ/HPCD by Maragos et al., [11], the interaction between the drug and the carrier would be sufficient enough to provide efficient solubilisation, but it would not limit its dissociation from the complex and consequent permeation. In summary, the presented results suggest that PZQ/HPCD complex prepared by mechanochemical activation could be regarded as a promising strategy to improve the biopharmaceutical properties of the drug.
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4. Conclusion The presented study clearly demonstrated the ability of the co-grinding procedure as a solvent free method suitable for the preparation of PZQ cocrystals and cyclodextrin complexes. All systems prepared showed increased solubility and dissolution properties of the drug, but in some cases, decrease of chemical and photostability was observed. Highly soluble amorphous binary complex of PZQ and HPCD showed acceptable chemical stability and biocompatibility, with permeability across the Caco-2 monolayer comparable to that of the free drug. This confirms that the mechanochemical drug activation in the presence of the proper co-grinding additive could be considered as a promising strategy to improve the biopharmaceutical properties of poorly soluble drugs, such as PZQ. Conflict of interest The authors report no conflicts of interests. Acknowledgment The financial support by the University of Zagreb (grant number BM072) and Croatian Science Foundation (grant numbers IP-201409-4841 and IP-2014-09-7367) are greatly acknowledged. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jpba.2017.01.025. References [1] E.D. Costa, J. Priotti, S. Orlandi, D. Leonardi, M.C. Lamas, T.G. Nunes, H.P. Diogo, C.J. Salomon, M.J. Ferreira, Unexpected solvent impact in the crystallinity of praziquantel/poly(vinylpyrrolidone) formulations. A solubility, DSC and solid-state NMR study, Int. J. Pharm. 511 (2016) 983–993. [2] J. Li, Y. Wang, A. Fenwick, T.A. Clayton, Y.Y.K. Lau, C. Legido-Quigley, J.C. Lindon, J. Utzinger, E. Holmes, A high-performance liquid chromatography and nuclear magnetic resonance spectroscopy-based analysis of commercially available praziquantel tablets, J. Pharm. Biomed. Anal. 45 (2007) 263–267. [3] A. Dayan, Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics, Acta Trop. 86 (2003) 141–159. [4] M. Woelfle, J.P. Seerden, J. de Gooijer, K. Pouwer, P. Olliaro, M.H. Todd, Resolution of praziquantel, PLoS Negl. Trop. Dis. 5 (2011) 1–7. [5] S. Joseph, F.M. Jones, K. Walter, A.J. Fulford, G. Kimani, J.K. Mwatha, T. Kamau, H.C. Kariuki, F. Kazibwe, E. Tukahebwa, N.B. Kabatereine, J.H. Ouma, B.J. Vennervald, D.W. Dunne, Increases in human t helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel, J. Infect. Dis. 190 (2004) 835–842. [6] Z.H. Wu, M. ke Lu, L.Y. Hu, X. Li, Praziquantel synergistically enhances paclitaxel efficacy to inhibit cancer cell growth, PLoS One 7 (2012) e51721. [7] R. Hayeshi, C. Masimirembwa, S. Mukanganyama, A.L.B. Ungell, The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux, Eur. J. Pharm. Sci. 29 (2006) 70–81. [8] G.E. Dinora, R. Julio, C. Nelly, Y.M. Lilian, H.J. Cook, In vitro characterization of some biopharmaceutical properties of praziquantel, Int. J. Pharm. 295 (2005) 93–99. [9] G. Becket, L.J. Schep, M.Y. Tan, Improvement of the in vitro dissolution of praziquantel by complexation with ␣-, - and ␥-cyclodextrins, Int. J. Pharm. 179 (1999) 65–71. [10] M.B. de Jesus, L. de Matos Alves Pinto, L.F. Fraceto, Y. Takahata, A.C.S. Lino, C. Jaime, E. de Paula, Theoretical and experimental study of a praziquantel and beta-cyclodextrin inclusion complex using molecular mechanic calculations and H1-nuclear magnetic resonance, J. Pharm. Biomed. Anal. 41 (2006) 1428–1432. [11] S. Maragos, H. Archontaki, P. Macheras, G. Valsami, Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel, AAPS PharmSciTech 10 (2009) 1444–1451. [12] S.G. Rodrigues, I.D.S. Chaves, N.F.S. De Melo, M.B. De Jesus, L.F. Fraceto, S.A. Fernandes, E. De Paula, M.P. De Freitas, L.D.M.A. Pinto, Computational analysis and physico-chemical characterization of an inclusion compound between praziquantel and methyl--cyclodextrin for use as an alternative in the treatment of schistosomiasis, J. Incl. Phenom. Macrocycl. Chem. 70 (2011) 19–28.
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