scholarly journals Molecular architectures of new inorganic lamivudine salts, an anti-HIV drug.

2014 ◽  
Vol 70 (a1) ◽  
pp. C1027-C1027
Author(s):  
Juan Tenorio ◽  
Javier Ellena
Keyword(s):  
Crystal Engineering ◽  
Vibrational Analysis ◽  
Scanning Calorimetry ◽  
X Ray ◽  
Pharmaceutical Ingredients ◽  
Pharmaceutical Form ◽  
Pharmaceutical Properties ◽  
Crystalline Forms ◽  
Ir And Raman ◽  
Anti Hiv

One of the currently goals of the crystal engineering is the improvement of pharmaceutical properties of Active Pharmaceutical Ingredients. Herein is discussed the design of new solid forms of the Lamivudine (3TC), one of the most used and marketed anti-HIV drug. The crystalline forms herein presented correspond to inorganic acid salts: Lamivudine hydrobromide (3TCH+-Br-), hydrogen difluoride (3TCH+-F-HF) and nitrate (3TCH+-NO3-). These new salts crystallized in non-centrossymetric space group P21. The halogenated salts (3TCH+-Br-and 3TCH+-F-HF) exhibited isostructural supramolecular assemblies, similar to the anhydrous salt of lamivudine hydrochloride (3TCH+-Cl-) reported by our research group, and whose equilibrium solubility showed an increase when compared with 3TC pharmaceutical form. [1,2] The main feature of the salt crystalline assemblies is related to the supramolecular ordering of the 3TCH+cationic units, by observing the formation of vacancies between them generated in the [100] direction due to the helical symmetry, so, the anions are localized into the interstices of these vacancies, stabilizing the crystalline assemblies. Meanwhile, the 3TCH+NO3-salt showed a different conformational and supramolecular behavior from that observed in the halogenated ones. Here is observed the formation of helical strands along the b axis, which will be engaging by translational symmetry in the horizontal direction in the [10-1] plane. Therefore, they form zigzag molecular planes which will subsequently be architected in parallel with the [10-1] direction. In addition, it was used for this study X-ray powder diffraction (XRDP), vibrational analysis: Infrared (IR) and Raman spectroscopy, and thermal analysis: differential scanning calorimetry (DSC), thermogravimetry (TG) and hot-stage microscopy. Comparison of the structural properties of these salts with some forms already reported (e.g. 3TCH+-Cl-) allows to infer some possible pharmaceutical properties.

CO-CRYSTALLIZATION: TECHNIQUE FOR IMPROVEMENT OF PHARMACEUTICAL PROPERTIES

INDIAN DRUGS ◽  
2016 ◽  
Vol 53 (09) ◽  
pp. 5-11
Author(s):  
S. S Pekamwar ◽  
◽  
D. D. Gadade ◽  
G. K. Kale
Keyword(s):  
Crystal Engineering ◽  
Solid Dispersions ◽  
Physicochemical Characteristics ◽  
Potential Effect ◽  
Drug Formulation ◽  
Intrinsic Activity ◽  
Active Pharmaceutical Ingredients ◽  
Pharmaceutical Ingredients ◽  
Physical Form ◽  
Pharmaceutical Properties

Physicochemical characteristics of active pharmaceutical compounds, including solubility and flow properties, are crucial in the development of drug formulation. The physical form of compound and formulation has potential effect on biopharmaceutical parameters of the drug. The crystal engineering approach can be employed for modification of physicochemical properties of the active pharmaceutical ingredients whilst maintaining the intrinsic activity of the drug molecule. This article covers the advantages of co-crystals over salts, solvates (hydrates), solid dispersions and polymorphs, mechanism of formation of co-crystals, methods of preparation of co-crystals and application of co-crystals to modify physicochemical characteristics of active pharmaceutical ingredients along with case studies.

scholarly journals Phase transitions in efavirenz induced by mechanical activation

2014 ◽  
Vol 70 (a1) ◽  
pp. C1565-C1565
Author(s):  
Alcemira Oliveira ◽  
Alejandro Ayala
Keyword(s):  
Thermal Analysis ◽  
Reverse Transcriptase ◽  
Room Temperature ◽  
Experimental Methodology ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Scientific Publications ◽  
X Ray ◽  
Crystalline Forms ◽  
Anti Hiv

Efavirenz,(S)-6-chloro-4(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, is a anti HIV agent belonging to the class of the non-nucleoside reverse transcriptase inhibitors, which is used in combination with other protease inhibitors or nucleoside reverse transcriptase inhibitors. Several polymorphs were reported in patents and scientific publications, being form I the thermodynamically most stable and the selected for commercial formulations. Mechanochemistry has emerged as an experimental methodology to efficiently and rapidly screen for new solid forms of a pharmaceutical active ingredient. These methods include neat and drop assisted grinding have been successfully applied to produce solvates, polymorphs, salts and cocrystals. In this contribution, we investigate the structural stability of efavirenz under mechanochemistry conditions. Room temperature and cryogenic neat and drop assisted grinding were applied to induce new crystalline forms, which were characterized by x-ray powder diffraction, vibrational spectroscopy and thermal analysis. The mechanism involved in these transformations were also investigated and discussed.

scholarly journals Evaluation of Thermal-Induced Polymorphic Transformation on Desloratadine and Desloratadine-Benzoic Acid Salt

2020 ◽  
Vol 26 (4) ◽  
pp. 399-405
Author(s):  
Ahmad Ainurofiq ◽  
Rachmat Mauludin ◽  
Diky Mudhakir ◽  
Sundani Nurono Soewandhi
Keyword(s):  
Melting Point ◽  
Benzoic Acid ◽  
Polymorphic Transformation ◽  
Heating Process ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
X Ray ◽  
Pharmaceutical Ingredients ◽  
Physicochemical Changes ◽  
Transformation Methods

Background: Active pharmaceutical ingredients face a challenge in manufacturing due to adverse physicomechanical properties. Desloratadine (DES) form I exhibits poor mechanical behavior through the formation of capping during the tableting process. Salt formation from DES and benzoic acid (BA) has been observed to resolve poor mechanical properties. However, the ability to withstand heat from the manufacturing process should be implemented in DES and DES-BA salt. The aim of this study was to determine the differences between thermal treatment results on DES and DES-BA salt and whether it causes them to undergo polymorphic transformation. Methods: Salt was crystallized between DES and BA using the solvent evaporation method. DES and DES-BA salt were heated at 110°C, 159°C (melting point of DES), 181°C (melting point of DES-BA), and 190°C. Following this, characterization was performed using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and solubility testing. Results: Polymorphic transformation caused by heat occurred in DES, but not in DES-BA salt. The transformation of DES was induced by the effect of heating, which changed polymorph I to a mixture of polymorph I and III at 110°C, to polymorph II at 159°C, and to a mixture of polymorph I, II, and III at 190°C. Under 190oC, DES-BA is still stable and did not undergo a polymorphic transformation. However, at 190oC, decomposition started to occur, which implied decreased solubility, which did not occur in DES. Conclusion: The heating process did not cause DES-BA salt to undergo a polymorphic transformation. However, it caused decomposition at 190oC. DES underwent a polymorphic transformation when exposed to the same condition without decomposition. This provided information to always pay attention to temperature during manufacturing processes that include DES or DES-BA salt to avoid physicochemical changes.

scholarly journals Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity

IUCrJ ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. 105-112 ◽  
Author(s):  
Syeda Saima Fatima ◽  
Rajesh Kumar ◽  
M. Iqbal Choudhary ◽  
Sammer Yousuf
Keyword(s):  
Crystal Engineering ◽  
Geometric Analysis ◽  
Biological Properties ◽  
Urease Inhibition ◽  
Inhibition Activity ◽  
Scanning Calorimetry ◽  
Pharmaceutical Ingredients ◽  
Crystal Stability ◽  
Urease Inhibition Activity

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methylideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thiourea by liquid-assisted grinding. The purity and homogeneity of the exemestane–thiourea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N—H...O hydrogen bonding between the amine (NH2) groups of thiourea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml−1) compared with the API (exemestane), which was found to be inactive, and the co-former (thiourea) (IC50 = 21.0 ± 1.25 µg ml−1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

scholarly journals Improved Solubility of Vortioxetine Using C2-C4 Straight-Chain Dicarboxylic Acid Salt Hydrates

Crystals ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 352 ◽  
Author(s):  
Lei Gao ◽  
Xian-Rui Zhang ◽  
Shao-Ping Yang ◽  
Juan-Juan Liu ◽  
Chao-Jie Chen
Keyword(s):  
Dicarboxylic Acid ◽  
Crystal Engineering ◽  
Dicarboxylic Acids ◽  
Acid Salt ◽  
X Ray Diffraction ◽  
Straight Chain ◽  
Scanning Calorimetry ◽  
X Ray ◽  
Salt Hydrates ◽  
Aliphatic Dicarboxylic Acids

The purpose of this study was to improve the solubility of vortioxetine by crystal engineering principles. In this paper, three C2-C4 straight-chain dicarboxylic acid salt hydrates of vortioxetine (VOT-OA, VOT-MA-H2O, and VOT-SUA-H2O, VOT = vortioxetine, OA = Oxalic acid, MA = malonic acid, SUA = succinic acid) were synthesized and characterized by single X-ray diffraction, powder X-ray diffraction, and differential scanning calorimetry. The single crystal structure of three salts reveals that vortioxetine has torsional flexibility, which can encourage VOT to allow combination with aliphatic dicarboxylic acids through N+-H···O hydrogen bonds. The solubility of all salts exhibits a dramatic increase in distilled water, especially for VOT-MA-H2O salt, where it shows the highest solubility, by 96-fold higher compared with pure vortioxetine.

Crystal Engineering in the design of New Solid Pharmaceutical Forms with enhanced pharmaceutical properties

2021 ◽  
Vol 4 (03) ◽  
pp. 72-80
Author(s):  
Javier Ellena
Keyword(s):  
Crystal Engineering ◽  
High Efficiency ◽  
National Health System ◽  
Pharmaceutical Formulations ◽  
Innovative Strategy ◽  
Pharmaceutical Ingredients ◽  
Pharmacokinetic Properties ◽  
Biological Target ◽  
Pharmaceutical Properties ◽  
And Performance

High-efficiency drugs and pharmaceutical formulations, produced in a sustainable way, and that present a favorable performance are widely required in Public Health. Among the pharmacokinetic properties of active pharmaceutical ingredients (APIs), the solubility is main variable since it regulate the availability in the biological target. Numerous formulations on the market and in the National Health System (SUS) present serious drawbacks related to quality, manufacture and performance. In general, APIs are delivered in solid formulations and this characteristic represents a challenge for industry and academia since the therapeutic efficiency of and APIs is related to their crystalline structure, i.d structural multiplicity, polymorphism and composition. APIs may exist in different forms presenting different pharmacokinetic profiles. In addition, the characterization of the diversities of solid forms of an IFA, constitutes an innovative strategy to optimize pharmaceutical properties, providing opportunities for the creation of intellectual property and innovation for the country. In this work we will discuss several strategies related to the problem aiming to show the importance in the pharmaceutical area of solid state techniques like crystal engineering.

scholarly journals Pharmaceutical Salts of Enrofloxacin with Organic Acids

Crystals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 646
Author(s):  
Hong Pang ◽  
Yu-Bin Sun ◽  
Jun-Wen Zhou ◽  
Meng-Juan Xie ◽  
Hao Lin ◽  
...  
Keyword(s):  
High Performance ◽  
Water Solubility ◽  
Antibacterial Drug ◽  
Mixed Solution ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
Organic Salts ◽  
X Ray ◽  
Poorly Soluble ◽  
Pharmaceutical Properties

Enrofloxacin is a poorly soluble antibacterial drug of the fluoroquinolones class used in veterinary medicine. The main purpose of this work was to investigate the structural and pharmaceutical properties of new enrofloxacin salts. Enrofloxacin anhydrate and its organic salts with tartaric acid, nicotinic acid and suberic acid formed as pure crystalline anhydrous solids. All the crystals were grown from a mixed solution by slow evaporation at room temperature. These products were then characterized by field-emission scanning electron microscopy, powder X-ray diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry. Further, X-ray single crystal diffraction analysis was used to study the crystal structure. The intermolecular interactions and packing arrangements in the crystal structures were studied, and the solubility of these salts in water was determined using high-performance liquid chromatography. The results show that the new salts of enrofloxacin developed in this study exhibited excellent water solubility.

scholarly journals Interconvertible Hydrochlorothiazide–Caffeine Multicomponent Pharmaceutical Materials: A Solvent Issue

Crystals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1088
Author(s):  
Cristóbal Verdugo-Escamilla ◽  
Carolina Alarcón-Payer ◽  
Antonio Frontera ◽  
Francisco Javier Acebedo-Martínez ◽  
Alicia Domínguez-Martín ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Intermolecular Forces ◽  
Active Pharmaceutical Ingredients ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
Great Stability ◽  
X Ray ◽  
Pharmaceutical Ingredients ◽  
Interesting Approach ◽  
Pharmaceutical Materials

The design of new multicomponent pharmaceutical materials that involve different active pharmaceutical ingredients (APIs), e.g., drug-drug cocrystals, is a novel and interesting approach to address new therapeutic challenges. In this work, the hydrochlorothiazide-caffeine (HCT–CAF) codrug and its methanol solvate have been synthesized by mechanochemical methods and thoroughly characterized in the solid state by powder and single crystal X-ray diffraction, respectively, as well as differential scanning calorimetry, thermogravimetric analyses and infrared spectroscopy. In addition, solubility and stability studies have also been performed looking for improved physicochemical properties of the codrug. Interestingly, the two reported structures show great similarity, which allows conversion between them. The desolvated HCT–CAF cocrystal shows great stability at 24 h and an enhancement of solubility with respect to the reference HCT API. Furthermore, the contribution of intermolecular forces on the improved physicochemical properties was evaluated by computational methods showing strong and diverse H-bond and π–π stacking interactions.

scholarly journals Melting Diagrams of Adefovir Dipivoxil and Dicarboxylic Acids: An Approach to Assess Cocrystal Compositions

Crystals ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 70 ◽  
Author(s):  
Hyunseon An ◽  
Insil Choi ◽  
Il Kim
Keyword(s):  
Solid State ◽  
Adefovir Dipivoxil ◽  
Sufficient Conditions ◽  
Dicarboxylic Acids ◽  
Current Approach ◽  
X Ray Diffraction ◽  
Scanning Calorimetry ◽  
X Ray ◽  
Pharmaceutical Ingredients ◽  
Solution Crystallization

Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification is not always unambiguous if cocrystallization is performed in solid state with unsuccessful solution crystallization. Single melting point and some new X-ray diffraction peaks are necessary but not sufficient conditions. In the present study, the use of melting diagrams coupled with the X-ray diffraction data was tested to identify cocrystal compositions. Adefovir dipivoxil (AD) was used as a model API, and succinic acid (SUC), suberic acid (SUB), and glutaric acid (GLU) were coformers. Compositions of AD/SUC and AD/SUB had been previously identified as 2:1 and 1:1, but that of AD/GLU was not unambiguously identified because of the difficulty of solution crystallization. Melting diagrams were constructed with differential scanning calorimetry, and their interpretation was assisted by powder X-ray diffraction. The cocrystal formation was exhibited as new compositions with congruent melting in the phase diagrams. This method correctly indicated the previously known cocrystal compositions of AD/SUC and AD/SUB, and it successfully identified the AD/GLU cocrystal composition as 1:1. The current approach is a simple and useful method to assess the cocrystal compositions when the crystallization is only possible in solid state.

scholarly journals Assembling the Puzzle of Taxifolin Polymorphism

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5437
Author(s):  
Roman P. Terekhov ◽  
Irina A. Selivanova ◽  
Nonna A. Tyukavkina ◽  
Igor R. Ilyasov ◽  
Anastasiya K. Zhevlakova ◽  
...  
Keyword(s):  
Crystal Engineering ◽  
Solid Phase ◽  
Active Pharmaceutical Ingredients ◽  
Amorphous Substance ◽  
X Ray ◽  
Pharmaceutical Ingredients ◽  
Solid States ◽  
Polymorphic Modifications ◽  
Xrpd Patterns ◽  
Scanning Electron

A large amount of the current literature dedicated to solid states of active pharmaceutical ingredients (APIs) pays special attention to polymorphism of flavonoids. Taxifolin (also known as dihydroquercetin) is an example of a typical flavonoid. Some new forms of taxifolin have been reported previously, however it is still unclear whether they represent polymorphic modifications. In this paper, we tried to answer the question about the taxifolin polymorphism. Taxifolin microtubes and taxifolin microspheres were synthesized from raw taxifolin API using several methods of crystal engineering. All forms were described with the help of spectral methods, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and thermal analysis (TA). SEM reveals that the morphology of the solid phase is very specific for each sample. Although XRPD patterns of raw taxifolin and microtubes look similar, their TA profiles differ significantly. At the same time, raw taxifolin and microspheres have nearly identical thermograms, while XRPD shows that the former is a crystalline and the latter is an amorphous substance. Only the use of complex analyses allowed us to put the puzzle together and to confirm the polymorphism of taxifolin. This article demonstrates that taxifolin microtubes are a pseudopolymorphic modification of raw taxifolin.

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