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Rosuvastatin cocrystals: an attempt to modulate physicochemical parameters
Future Journal of Pharmaceutical Sciences volume 7, Article number: 64 (2021)
The meager physicochemical properties like low solubility and low dissolution rate of rosuvastatin calcium remain as an obstruction for formulation development. In the present work, we explore the evolution of rosuvastatin cocrystal, which may offer the synergetic physico-chemical properties of the drug. Cocrystal crafting depends on two possible intermolecular interactions; heteromeric and the homomeric selection of compounds with complementary functional groups are contemplated as a possible cause of supramolecular synthons in cocrystal formation. Specifically, cocrystals of rosuvastatin with l-asparagine and l-glutamine with molar ratio (1:1) were fabricated by using slow solvent evaporation and slow evaporation techniques. Novel cocrystals of rosuvastatin-asparagine (RSC-C) and rosuvastatin-glutamine (RSC-G) cocrystals obtained by slow solvent evaporation were utilized for preliminary investigation and further scale-up was done by using the solvent evaporation technique.
The novel cocrystals showed a new characteristic of powder X-ray diffraction, thermograms of differential scanning calorimetry, 1H liquid FT-NMR spectra, and scanning electron microscopy. These results signify the establishment of intermolecular interaction within the cocrystals. In both the novel cocrystals, rosuvastatin was determined to be engaged in the hydrogen bond interaction with the complementary functional groups of l-asparagine and l-glutamine. Compared with the pure rosuvastatin, RSC-C and RSC-G cocrystal showed 2.17-fold and 1.60-fold improved solubility respectively. The dissolution test showed that the RSC-C and RSC-G cocrystal exhibited 1.97-fold and 1.94-fold higher dissolution rate than the pure rosuvastatin in pH6.8 phosphate buffer respectively.
Modulation in the chemical environment, improvement in the solubility, and dissolution rate demonstrated the benefit of co-crystallization to improve the physicochemical properties of the drug.
Among all the physicochemical properties of the active moiety, dissolution and solubility are well deliberated to be the rate-determining step of poorly water-soluble drugs during oral absorption. Method selection for solubility and dissolution rate enhancement is crucial in attaining good oral absorption. Considering different methods, pharmaceutical cocrystals offers the most promising approach to improve physicochemical properties of the active moiety like solubility, melting point, dissolution, and stability [1, 2]. Pharmaceutical cocrystals are multi-component complexes containing two or more molecules [3, 4]. The main edge in cocrystal formation is the adjustment of physicochemical properties of drug molecules through alteration in its supramolecular structure, without a change in its covalent structure . An important aspect in cocrystal crafting depends on two possible intermolecular interaction heteromeric and the homomeric selection of components with complementary functional groups that are contemplated as a possible cause of supramolecular synthons in cocrystal formation [6, 7]. The co-crystallization approach is a well productive choice that notably furnishes the active molecule with required physicochemical properties [8, 9] and also donates the right of intellectual property protection . Furthermore, accompanying high capability without waste products and causing co-crystallization and an influential chunk of Green chemistry .
Preparation methods of cocrystals include precipitation, sublimation, solution crystallization, and solvent evaporation [12,13,14]. In the solvent-free technique, the intermittent phase is formed by co-grinding of the drug and co-former . Along with the above approaches, various other techniques are also hired for the development of cocrystals such as super-critical fluids, sonic slurring, hot-melt extrusion, wet and dry compression, and ultrasound [16,17,18].
Rosuvastatin, (E,3R,5S)-7-(4-(4-fluorophenyl)-2-(methyl(methylsulfonyl)amino)-6-propan-2-ylpyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate has been utilized for the treatment of hyperlipoproteinemia, hypercholesterolemia, atherosclerosis, and avoidance of coronary heart diseases which belongs to BCS class-II drugs [19, 20]. Rosuvastatin comes under the statin family, known as “super statin” [21, 22], which contains two oxydrilic group bound to asymmetric carbon atoms which are part of side-chain linked to a pyrimidine ring. The major trouble with this drug is low water solubility (0.33 mg/ml) which displays low solubility in gastrointestinal fluids . Previously, various efforts to enhance the solubility of rosuvastatin such as polymerization , liquisolid technology , and nano-emulsifying delivery systems  were ample in the literature. Cocrystals of rosuvastatin were formulated by utilizing sorbitol  and vanillin  as co-formers. These cocrystal inventions provided the feasibility in utilizing the rosuvastatin cocrystals to modulate and design better product . Ferrori et al. 2014 utilized three different rosuvastatin co-crystal such as Rosuvastatin 2-aminopyrimidine hemihydrate, Rosuvastatin pyrazine hydrate, and Rosuvastatin quinoxaline in the rosuvastatin synthesis process .
Amino acids are Zwitterionic compounds that exist under the GRAS group with low hazardous to the biological system in comparison with other co-formers [31, 32]. Moreover, their zwitterionic potentialities could form charge-assisted hydrogen bondings in cocrystal formation [33, 34]. Based on the synthon approach, cocrystal formation mainly depends upon the functional groups that are present in the drug molecule and the co-former [35, 36]. Carboxyl groups and amino groups present in amino acids act as good hydrogen bond acceptors and donors respectively, so these may be the satisfying co-former candidate for rosuvastatin cocrystal formulation.
In the present investigation, two amino acids containing the amide group, shown in Fig. 1, are preferred to form cocrystal with rosuvastatin. Specifically, cocrystals of RSC with l-asparagine and l-glutamine were synthesized by the solvent evaporation technique. For the novel cocrystals, structural characterization was done by powder x-ray diffraction (PXRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), 1H liquid FT-NMR, and scanning electron microscopy (SEM). In vitro evaluations were done by aqueous solubility and in vitro dissolution drug release and these were compared with the parent drug molecule.
Rosuvastatin calcium (RSC), l-asparagine, and l-glutamine were procured from Lotus chemicals (Andhra Pradesh, India). Methanol (chromatographic grade) was procured from Balda chemicals (Andhra Pradesh, India). All other chemicals utilized in the study were of commercial grade.
Rosuvastatin is characterized by the presence of two-oxydrilic groups bound to asymmetric carbon atoms which are part of a side chain linked to a pyrimidine ring, presented in Fig. 1. Considering rosuvastatin functional groups, co-former having an amide group may have the chance of forming hydrogen bonds. l-asparagine and l-glutamine are the amide-containing compounds and also Zwitterionic compounds were selected for the present study.
Synthesis of novel cocrystals
Slow solvent evaporation
The cocrystals are produced by a molar ratio of 1:1 was as given: RSC (500 mg) with ASN (140 mg) and GLN (156 mg). The drug and the conformer were dissolved in a 3:1 ratio of ethanol and water in the test tube. The container was sealed with aluminium foil and 3 to 4 holes were stabbed on the foil for slow evaporation. The container was placed in the desiccator for 2 to 3 days and the cocrystals obtained were utilized for preliminary investigation.
Two novel cocrystals of rosuvastatin calcium with l-asparagine and l-glutamine were prepared by the solvent evaporation technique. The cocrystals are produced by a molar ratio of 1:1 was as given: RSC (500 mg) with ASN (140 mg) and GLN (156 mg). The drug was dissolved in 15 ml of methanol and the co-former in 5 ml of distilled water. Both the solutions were stirred, and then ultrasonicated until the material was completely dissolved to form a clear solution. Methanol solution containing RSC was placed on the magnetic stirrer and the aqueous solution containing co-former was added dropwise. The stirring was continued until the solvent was completely evaporated. The product formed was placed in a desiccator overnight for complete drying of the cocrystals.
Fourier transform infrared spectroscopy analysis
Fourier transform infrared spectroscopy spectra of RSC, ASN, GLU, RSC-C, and RSC-G is recorded using Azilent 360 series spectrometer containing DLATGS detector with 2 cm−1 spectral resolution. Then, 2–4 mg of each sample was placed on the sample cell and scanned through the wavelength of 4000–400 cm−1. The obtained data was analyzed using spectrum software.
Differential scanning calorimetry analysis
The thermal behavior of the samples was analyzed by utilizing differential scanning calorimetry. Each sample (4–5 mg) of pure drug, co-formers, and novel cocrystals were scanned by using Mettler Teledo DSC 8221e calorimetry. Each sample was sealed in aluminium sample pan, and an empty sealed aluminium pan was used as a reference. All the samples were scanned at a rate of 10 °C min−1 starting from 25 to 350 °C under nitrogen purge (30 ml/min).
Powder X-ray diffraction analysis
Crystalline structure alterations of RSC and novel cocrystals were analyzed by utilizing powder XRD diffractometer. Each sample of the pure drug, co-formers, and the cocrystals were placed in the sample holder then scanned by utilizing Philips Xpert MPD diffractometer with Cu target X-ray tube source which was operated at 30 kV and 15 mA for 2Ө scan axis. Maintaining a 5–65° scan range with 0.02° of step width and 10.00°/min scan speed.
1H liquid FT-NMR analysis
1H liquid FT-Nuclear Magnetic resonance spectra for RSC, ASN, GLU, RSC-C, and RSC-G is recorded by utilizing 400 MHz FT-NMR spectrometer (JNM-ECZ 400S) USINF TMS as an internal standard. Each sample was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) for analysis and operated at 400 MHz frequency. The obtained spectra were integrated using JEOL Delta software.
Scanning electron microscopy analysis
Morphological changes between the pure drug RSC and the novel cocrystals were analyzed with scanning electron microscopy. Scanning electron microscopy (SEM) analysis was done by using XL30ESEM with EDAX containing backscattered and secondary electron detectors. The particles were prepared for the analysis by placing on aluminium stabs and coated with gold under vacuum. The samples were photomicrographed at different magnifications.
In vitro evaluation
The equilibrium method  was utilized for determining the apparent solubility of pure drug RSC, cocrystals RSC-C, and RSC-G. An excess amount of each sample was placed in vials with caps containing 10 ml of pH 6.8 phosphate buffer. These solutions were sonicated for 15 min and were placed in a water bath shaker for 48 h with a rotating speed of 200 rpm at 30 ± 1 °C. The supernatant solution was filtered through 0.45 μm filters. This filtrate was diluted with methanol and the drug concentration was determined by utilizing UV-Spectrophotometer (V-630, Jasco. Japan) at 244 nm. Apparent solubility analysis was conducted in triplicate and the residual solids were qualitatively analyzed by Fourier transform infrared spectroscopy (FT-IR).
In vitro dissolution study
The in vitro drug release studies were carried out triplicate in Erweka DT600 USP apparatus-II (paddle method). The highest dose of RSC (40 mg), RSC-C, and RSC-G (Equivalent to 40 mg of pure drug) was put into 900 ml of dissolution media. The paddles were rotated at 100 rpm by maintaining 37 ± 0.5 °C throughout the study. Two milliliters of aliquot was collected at 10, 20, 40, 80, and 120 by replacing with fresh dissolution medium. Collected aliquots were filtered through a 0.45 μ filter; the filtrate was diluted and estimated for drug concentration using UV-Spectrophotometer (V-630, Jasco. Japan) at 244 nm.
Fourier transform infrared spectroscopy
Alterations of intermolecular interactions in comparison to parent molecules can be studied using FT-IR . Figure 2 shows the FT-IR spectra of starting materials and novel cocrystals. For RSC, the characteristic peaks corresponding to carboxylic O-H stretch and N-H stretch are assigned at 3382, 2968 cm−1 respectively . For ASN, a sharp peak appeared at 3378 cm−1 was assigned to O-H stretch, and a broad multiple peaks at 3099 was ascribed as N-H stretch . For GLN, a characteristic O-H peak was assigned at 2401, and a broad multiple peaks corresponding to N-H stretch was ascribed at 3168 cm−1 [41, 42]. These are the main functional groups that are responsible for hydrogen bond formation.
The FTIR analysis RSC-C cocrystals showed the shift in the O-H peak position of parent molecule from 3382 cm−1 to and nitrogen peak of ASN from 3099 to 3369 cm−1; meanwhile, the carbonyl group shift from 1654 to 1686. RSC-G cocrystals exhibited a shift in the O-H peak of RSC from 3382 and nitrogen peak of GLN from 3213 to 3401; meanwhile, the carbonyl group shifted from 1654 to 1684. A similar type of shift can be noticed in both the novel cocrystals indicating a similar type of interaction.
Differential scanning calorimetry
The cocrystals of RSC-C and RSC-G formulated by the solvent evaporation technique were analyzed for their thermal behavior concerning the starting compounds. Differential scanning calorimetry (DSC) was widely used in investigating the compatibility status and structural alterations in the molecule . DSC thermograms of the starting material and novel cocrystals were shown in Fig. 3. RSC presented an endothermic peak between 65 and 80 °C, which is considered as a water loss peak, to the next RSC showed multiple endothermic melting peaks between 230 and 300 °C displaying the semi-crystalline structure of the molecule . Co-formers ASN and GLN showed a sharp endothermic melting peak at 241 °C and 193 °C respectively.
In RSC-C novel cocrystal broad endothermic between 60 and 80 °C indicates the lattice water existence and a sharp endothermic event at 129 °C ascribed as the melting point which is a major alteration when compared to the parent molecule. RSC-G cocrystal presented a sharp endothermic peak at 198 °C indicating the melting point deviation with the parent molecule. In both the cocrystal, the multiple endothermic melting peaks of the parent molecule have vanished, confirming the loss of semi-crystalline nature of the compound.
Powder X-ray diffraction
Most of the drugs exhibit various forms in their solid-state like crystalline, amorphous polymorphs, and solvates. In turn, these forms can vary extensively in their physicochemical properties . Along with the DSC, powder X-ray diffraction (PXRD) analysis has the ability to determine the crystallinity of the drug molecule. PXRD spectra of the starting materials and the novel cocrystals were shown in Fig. 4. PXRD pattern of RSC indicated the semi-crystalline nature of the molecule, which is in agreement with the previous literature .
RSC-C cocrystal showed the major characteristic peaks of 2Ɵ scattering angles at 9.14°, 10.28°, 20.85°, 24.61°, 32.93°, and 40.06° which were absent in the drug molecule and differ from co-former. RSC-G showed the major characteristics peaks of 2Ɵ scattering angles at 20.61°, 23.58°, 24.20°, 26.74°, 29.41°, 3.58°, 34.98°, 39.39°, and 40.95° which are new for RSC and differ from GLN.
1H liquid FT-NMR
Alteration in the chemical environment can be readily detected through the chemical shift in NMR spectrum. Both the Novel cocrystals, RSC-C and RSC-G, showed the co-existence of resonance peaks from the starting materials with significant chemical shift indicating the new phase generation . A solvent peak (DMSO-d6) at δ = 2.6 can be detected in both the starting materials and the co-crystals. Plain RSC showed the proton peaks at δ = 1.16, 2.10, 3.50, 3.35, 3.71, 6.45, 7.22, and 7.65, in which 3.35 and 3.71 are assigned to protons of two oxydrilic groups which are considered to be the main characteristic groups that involved in hydrogen bond interaction. All the proton peaks assigned were clearly indicated in Fig. 5. RSC-C cocrystals showed a major peak shift in these oxydrilic groups to 2.65 and 3.68 respectively. Whereas, RSC-G cocrystal exhibited the chemical shift in oxydrilic groups to 3.32 and 3.69 respectively.
Scanning electron microscopy
The habit of the starting materials and the novel cocrystals prepared from solvent evaporation as shown in Fig. 6. Plain RSC presented as plate-shaped particles with irregular surface morphology and random sizes. Co-formers ASN and GLN appeared as stick-shaped crystalline and with smooth surface morphology. In RSC-C cocrystals, the plate-shaped particles were converted to an irregular closely fitted crystalline structure. Whereas the RSC-G exhibited as stick-shaped closely fitted clusters. This alteration within the habit of the cocrystals might be due to the intermolecular hydrogen bonds between the drug and the co-former.
In vitro evaluation
The apparent solubility analysis was assessed for pure drug and the novel cocrystals in pH 6.8 phosphate buffer. Quantification of RSC was assessed by UV spectrophotometer, and the outcomes are presented in the Table 1. The samples were assessed after 4 h, 24 h, and 48 h as described in the “Methods” section. The solubility enhancement of the cocrystals was reduced after 4 h. The solubility of RSC cocrystals was presented to be very less after 24 h, and no solubility enhancement was seen after 48 h. This reduction may be due to the breakdown of cocrystals into its parent molecules.
Apparent solubility of novel cocrystals was compared with that of pure drug RSC. Plain RSC showed the solubility of 1.427 mg/ml, whereas RSC-C cocrystals exhibited 3.466 mg/ml which is almost 2.17-fold higher to that of the parent molecule, followed by RSC-G cocrystals that showed 2.283 mg/ml which is 1.64-fold higher to parent molecule within 4 h (Smax) of the solubility analysis. The residual material was analyzed by FT-IR after 4 h, 24 h, and 48 h to find any alterations in cocrystals. These results showed that there is no change in cocrystals up to 4 h; after 24 h, the FT-IR spectra of the residual materials find similar to that of the pure drug  which was shown in Fig. 7.
In vitro dissolution studies
The in vitro drug release profiles of RSC, RSC-ASN physical mixture, RSC-GLN physical mixture, RSC-C, and RSC-G were analyzed in pH 6.8 phosphate buffer and were shown in Fig. 8. In the media, the plain RSC, RSC-ASN physical mixture, and RSC-GLN physical mixture exhibited almost similar dissolution with 23.4% to 49.5%, 25.6% to 52.4%, and 24.9% to 50.8% drug release in 120 min respectively, which is in agreement with the previous literature . Whereas RSC-C and RSC-G cocrystals showed fastened and almost maximum drug release (> 80%) within 120 min of the study. RSC-C cocrystals exhibited 91.4% to 97.7% of the drug release within 120 min, which is almost 1.97-fold higher than that of pure drug. RSC-G cocrystals showed 84.6% to 86.3% of the drug release which is of 1.74-fold enhancement of drug release in comparison to pure drug. The studies pointed out the increased dissolution performance of RSC upon co-crystallization with l-asparagine and l-glutamine, which is in good agreement with apparent solubility studies.
Cocrystals are cognominated among the products that are obtained from the crystal engineering approach with ionic/non-covalent intermolecular interaction between two or more disparate molecules with a certain stoichiometric ratio in a crystal lattice [48, 49] at most one molecule should be active moiety. Generally, the choice of co-former should be done from GRAS (Generally recognized as safe) or EAFUS (Everything added to food in united states) list, which is frequently without pharmacological efficacy [50, 51]. Therefore, it contributes a practical approach in organizing the physicochemical properties with no medical efficacy diversity [52, 53]. The co-former selected should essentially carry a group able to develop molecular synthons with the active moiety. In this framework, amino acids appear to be a beneficial option as an applicable companion. Amino acids exist under the GRAS group, besides pretty low toxicity and inexpensive. Many of the salt, that is formed from the amino acids with various classes of therapeutic agents, were reported in previous literatures [54, 55].
The shift in the wavenumber points out the new chemical interactions of the drug and the co-former that impact the functional group position. Both the novel cocrystals show the O-H, which was converted to a broad single peak, and the nitrogen peak of the co-former was comparatively suppressed. This outcome confirms the merging of two functional groups through hydrogen bond formation between the hydroxyl group of the drug and nitrogen group of the co-former.
Based on the study of Perlovich , 55.3% of cocrystals exhibit the melting point in the middle, 28.9% of cocrystals with low, and 14.5% exhibit higher endotherm than the starting materials. RSC-C presented a melting point at 129 °C, which melts at the temperature below the melting point of the drug and the co-former. This decrease in enthalpy and melting point in comparison to pure compounds indicates the formation of the weak crystalline structure [57, 58]. RSC-G presented a melting point at 198 °C indicating the melting point of cocrystal is in the middle of the drug and the co-former, which is a very common phenomenon in 1:1 stoichiometric cocrystals .
In DSC study, the nature of the novel cocrystal is represented by the position and shape of endothermic melting peaks. The sharp and narrow endothermic peaks presented by novel cocrystal indicate a high degree of purity and crystallinity of formed non-covalent derivatives . The shift in the endothermic event within the formulation due to the alteration in the crystalline geometry of RSC induced by the interaction of free hydroxyl groups of RSC with the amine group of co-former. However, the presentation of peak distinctly indicates the absence of ionic interaction between the drug and the performer.
In PXRD analysis, the appearance of the new characteristic peaks in the novel cocrystals indicates the new phase generation. PXRD results confirm the conversion of the semi-crystalline nature of the drug into a new weak crystalline form in both the cocrystals. This new phase may be the cocrystal formation due to the hydrogen bond interaction between the drug and the co-former which was found to be in accordance with DSC and FT-IR studies.
Apparent solubility of novel cocrystals was compared with that of pure drug RSC. Plain RSC showed the solubility of 1.427 mg/ml, whereas RSC-C cocrystals exhibited 3.466 mg/ml which is almost 2.17-fold high to that of the parent molecule, followed by RSC-G cocrystals showed 2.283 mg/ml which is 1.64-fold high to parent molecule with within 4 h (Smax) of the solubility analysis.
In FT-NMR analysis, both the cocrystal showed the downfield nature of chemical shift values indicating the involvement of both oxydrilic groups in bond formation. This chemical shift value alteration confirmed the cocrystal formation between drug and the co-former probably due to the interaction of free hydroxyl groups of drug with co-formers. Furthermore, the outcomes attended by the FT-NMR analysis were in good agreement with DSC, PXRD, and FT-IR analysis.
This enhancement of solubility until 4 h is sufficient to increase the absorption of the drug. This mechanism is known as the spring and parachute effect showed by many of the cocrystals [60, 61]. According to this mechanism, after breaking down of cocrystals (after 4 h), the more soluble part (co-former) of cocrystal is drained out of the crystal lattice into the solution. While the drug component evolves supersaturated in biological medium. This increase in energy of the drug molecule is known as spring energy. This condition lasts for sufficient time (parachute effect) to facilitate proper absorption.
In in-vitro dissolution analysis, RSC-C and RSC-G cocrystals showed fastened and almost maximum drug release (> 80%) within 120 min of the study. RSC-C cocrystals exhibited 91.4% to 97.7% of the drug release within 120 min, which is almost 1.97-fold higher than that of pure drug. RSC-G cocrystals showed 84.6% to 86.3% of the drug release which is of 1.74-fold enhancement of drug release in comparison to pure drug. The studies pointed out the increased dissolution performance of RSC upon co-crystallization with l-asparagine and l-glutamine, which is in good agreement with apparent solubility studies. The strategy of converting the idea of cocrystals into the application was well explained in the previous literatures, which may be helpful for process development in the future investigation [62,63,64].
Although extensive research was dedicated to cocrystals, most of the literature reported novel cocrystal production and its modification in physicochemical properties; there is a lack of information regarding the selection of co-former and their effect on the biological system. Hence, the present study showed amino acids that exist under the GRAS group with low hazardous to the biological system as a suitable choice as co-former in cocrystal preparation. These amino acids, due to their zwitterionic potentialities, act as good hydrogen bond acceptors and donors. This study has demonstrated the formulation of rosuvastatin cocrystals through both l-asparagine and l-glutamine as the co-formers. The cocrystal structure alteration is compared with the spectral data of the parent molecule, implying the intermolecular interaction established within the cocrystals. In both cases, RSC was determined to be engaged in the hydrogen bond interaction with the complementary functional groups of ASN and GLN. Improvement in the solubility studies demonstrated the benefit of co-crystallization to improve the physicochemical properties. Furthermore, the outcomes of solubility analysis are in concurrence with the in vitro dissolution study. However, in the present investigation, the in vivo performance of the cocrystals like Cmax and AUC have not been covered and will be taken up in our next publication. The outcomes clearly indicate the modulation in the chemical structure, solubility enhancement, and dissolution enhancement of RSC through co-crystallization.
Availability of data and materials
The data generated or analyzed during this study are included in this article, if any excess data required will be available from the corresponding author on reasonable request.
Fourier transform infrared spectroscopy
Differential scanning calorimetry
Powder X-ray diffraction
FT-nuclear magnetic resonance
Scanning electron microscopy
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The authors are thankful to Maharajah’s college of pharmacy, Vizianagaram, Andhra Pradesh and Gitam deemed to be university for providing the facilities to carry the research work.
This research received no specific grant from any funding agency in public, commercial, or not-for-profit sector.
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Vemuri, V.D., Lankalapalli, S. Rosuvastatin cocrystals: an attempt to modulate physicochemical parameters. Futur J Pharm Sci 7, 64 (2021). https://doi.org/10.1186/s43094-021-00213-7
- Rosuvastatin calcium
- Solvent evaporation