WO2013095169A1 - Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide - Google Patents

Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide Download PDF

Info

Publication number
WO2013095169A1
WO2013095169A1 PCT/PT2012/000051 PT2012000051W WO2013095169A1 WO 2013095169 A1 WO2013095169 A1 WO 2013095169A1 PT 2012000051 W PT2012000051 W PT 2012000051W WO 2013095169 A1 WO2013095169 A1 WO 2013095169A1
Authority
WO
WIPO (PCT)
Prior art keywords
minocycline
chlorohydrate
carbon dioxide
resistant
crystalline
Prior art date
Application number
PCT/PT2012/000051
Other languages
French (fr)
Inventor
Miguel Ângelo Joaquim RODRIGUES
Luís Miguel Borges PADRELA
Henrique Aníbal Santos de MATOS
Edmundo José Simões Gomes de AZEVEDO
Lídia Maria Veloso PINHEIRO
Ana Francisca Campos Simão BETTENCOURT
Matilde Luz Santos Duque Fonseca E CASTRO
António José Leitão das Neves ALMEIDA
Maria Aida da Costa e Silva da Conceição DUARTE
Original Assignee
Instituto Superior Técnico
Universidade De Lisboa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PT106063A priority Critical patent/PT106063B/en
Priority to PT106063 priority
Application filed by Instituto Superior Técnico, Universidade De Lisboa filed Critical Instituto Superior Técnico
Publication of WO2013095169A1 publication Critical patent/WO2013095169A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00Systems containing at least three condensed rings
    • C07C2603/02Ortho- or ortho- and peri-condensed systems
    • C07C2603/40Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/461,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Abstract

The present invention relates to a novel form of minocycline chlorohydrate characterized in that- it is crystalline and it presents characteristic powder X-ray diffraction pattern and infrared spectrum. This new polymorph constitutes the most stable form of minocycline with a melting point much higher than that of other known crystalline forms of minocycline. The process of production of this new minocycline polymorphic form consists in the dissolution of carbon dioxide in solutions or suspensions of minocycline chlorohydrate with organic solvents, under certain conditions of pressure and temperature. The present invention places minocycline in the restrict group of antibiotics with a melting temperature higher than the sterilization temperature, which enhances new applications and allows the optimization of production at industrial

Description

DESCRIPTION
Crystalline Minocycline Thermo-resistant obtained by recrystallization with carbon dioxide
Field of the invention
This invention falls within the scope of new antibiotic crystalline forms and processes leading to its recrystallization. Particularly, it presents a novel crystalline form of minocycline with enhanced properties and describes the processes for its production with the use of anti-solvent effect caused by carbon dioxide.
Background of the invention
Antimicrobial drugs have been losing their effectiveness due to the adaptive evolution of microorganisms. The exaggerated use of antibiotics in the therapy has been pointed out as the leading cause of the emergence of resistant pathogenic agents and antibiotic multiresistance, compromising the fight against community- and hospital- acquired infections. The multiresistant species constitute the major concern in the field of surgical interventions, namely when a foreign body is implanted. Antibiotics are generally less effective treating infections along the surfaces of bone and artificial devices (due to the poor vascularization of bone tissue and the development of bacteria in the form of biofilms on implanted biomaterials surfaces) , leading to multidrug-resistant bacterial infections.
This problem can be significantly attenuated by materials impregnated with antibiotics for controlled and sustained drug release. However, for production of these materials, it is convenient to expose antibiotics to high temperature (either for polymerization, extrusion or sterilization) . Under this scope, the few heat-resistant (above 200 °C) antibiotics available restrict the formulations and antibiotic mixtures ("antibiotic cocktails"), susceptible to be incorporated in prostheses and implants, limiting therefore the antimicrobial effectiveness of the products. The existence of a crystalline minocycline thermo-resistant form which may be included in formulations used in the controlled and sustained delivery of this antibiotic, can be determinant in the therapy of associated infections to prostheses and implant placements, for example.
Minocycline is a broad-spectrum antibiotic long-acting semi-synthetic derivative of the antibiotic tetracycline, which inhibits the bacterial protein synthesis preventing the binding of aminoacyl-tRNA to the 30S bacterial ribosomal subunit. Among the several antibiotics for clinical use, minocycline (oral or intravenous administration) presents a broader spectrum when compared with other compounds from the tetracycline family. Minocycline is particularly indicated in the treatment of bone infections (among other applications) , concurring as well to a beneficial effect in the tissue regeneration processes. This antibiotic shows a relevant potential against bacterial multiresistant strains, namely methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter bau anii, accountable for a high number of community- and hospital-acquired infections. Minocycline also shows anti-inflammatory and anti-apoptotic effects, exhibiting neuroprotective properties in different neurodegenerative diseases. Minocycline is the most lipo- soluble of its class, effectively crossing the blood-brain barrier. The increased lipophilicity enhances minocycline penetration into various tissues when compared with other tetracyclines; therefore it is particularly suitable for material interfaces and subcutaneous implants, since it is not easily washed out to cause a burst effect. Instead, it is likely to stay active within the materials interface - a critical region for infection. This invention is a technological contribution to place minocycline in the restrict group of thermo-resistant antibiotics, complementing the weakness of other heat-resistant antibiotics, and leading thus to antibiotic-impregnated materials more active in treating infections.
Beyond the improved stability of minocycline mentioned before, this invention also improves the control of its crystalline form. The minocycline crystalline form is rather difficult to control, as evidenced by the thermogram of the commercial product (Sigma Aldrich, Germany) not recrystallized with carbon dioxide (C02) shown in Figure 1. For example, the mentioned commercial minocycline from Sigma Aldrich is a mixture of crystalline forms with the amorphous form. It is well-known that the mixture of polymorphs with amorphous forms is unstable and it is little reproducible because amorphous substances can react with excipients, moisture or convert into crystalline forms causing the product properties to be unpredictable and unstable. The changes in physicochemical properties (like chemical reactivity, solubility, dissolution rate, melting temperature, electrical and optical properties) compromise the bioavailbility of a bioactive compound of therapeutic utility, and consequently its efficacy. Since each crystalline form presents different properties (as: the amorphous form) , the actual formulations are heterogeneous and relatively unpredictable. During drugs synthesis process, polymorphic transformations may occur in the recrystallization stage, which defines the physicochemical properties of these bioactive compounds. The present invention enables the achievement of a crystalline minocycline thermo-resistant produced by a recrystallization with carbon dioxide. This novel crystalline form is pure and, in opposition to the commercially available formulations, it is not a mixture of crystalline forms with the amorphous form. On the other hand, the processes of recrystallization described in this invention constitute techniques that allow controlling effectively the crystalline minocycline form.
Most processes used to produce minocycline powders (such as the common technique to produce small particles of controlled size designated as spray-drying) are unable to control its crystalline form. To overcome this limitation, some inventors developed a crystallization process in order to recrystallize minocycline base into a crystalline structure of controlled form (patents PT 103661 A.2008-08- 25; WO 2008102161 A2.2008-08-28 ; US 20100286417 Al.2010-11- 11) . However, the developed process (WO2008102161) is laborious, because it involves several steps for the micronization, recrystallization and purification from organic solvents, and it is unable to produce the thermo- resistant polymorph of minocycline described in this invention, that is induced by carbon dioxide.
The production of this novel polymorph is based on the anti-solvent effect caused by carbon dioxide when the latter is added to solutions or suspensions of minocycline in organic solvents. The C02 anti-solvent effect has been used by many authors to micronize substances including its amorphization . Nevertheless, so far, the C02 anti-solvent effect was not used to control the crystalline minocycline form.
The process for the production of crystalline minocycline chlorohydrate referred in this invention, presents as advantages the production of a novel thermo-resistant polymorph and the potential of a more effective control of the crystalline form.
Summary of the Invention
The present invention relates to a novel form of minocycline chlorohydrate and to a process for its production. This novel form of minocycline is characterized in that it is crystalline, with characteristic powder X-ray diffraction pattern and infrared spectrum, and a melting temperature of 247 °C. The production process involves the mixing of. carbon dioxide with solutions or suspensions of minocycline chlorohydrate in organic solvents, under certain conditions of pressure, temperature and composition. The recrystallization method is based on the carbon dioxide anti-solvent effect. Briefly, the minocycline recrystallizes in solution or in suspension when the carbon dioxide composition in the mixture reaches the necessary composition to induce an anti-solvent effect. This new minocycline polymorph is characterized in that it has a melting temperature (247 °C) , which is about 50 °C to 130 °C higher than that of other known crystalline forms of minocycline. The high melting temperature enables to subject the novel crystalline minocycline chlorohydrate to heat sources, directly or embedded in other materials, either for sterilization effects (example: autoclaving) extrusion or polymerization. The microbiological studies performed against several reference and multiresistant bacterial strains, testified the antimicrobial activity preservation of the novel minocycline chlorohydrate polymorph, relatively to that of the product not processed with carbon dioxide.
Detailed description of the invention
This invention relates to a novel form of crystalline minocycline resistant to very high temperatures. The new polymorph is characterized in that it has a melting temperature of 247 °C (±1°C) , which is 50 °C to 130 °C higher than melting and degradation temperatures of other known crystalline forms of minocycline. Given these characteristic thermophysical properties, the new polymorph related to this invention can be embedded in composite materials, prostheses, bone cements, implants and controlled drug delivery formulations, as well as in sterile pharmaceutical formulations or compositions (namely when concerning damp heat sterilizations) .
The process of minocycline chlorohydrate production, which is also related to the present invention, is characterized in that it has the mixture of carbon dioxide with organic solvents and minocycline chlorohydrates under certain conditions of pressure, temperature and composition above the corresponding saturation conditions of minocycline in the mixture (determined by phase equilibria) .
The novel form of crystalline minocycline thermo-resistant is also characterized in that it presents an X-ray diffraction pattern having peaks at 5.5, 9.6, 11.0, 13.5, 15.6, 15.8, 16.5, 16.8, 17.4, 18.3, 19.0, 19.2, 20.8, 22.0, 22.2 e 23.3 +0.2° 2Θ , as given in Figure 3. It is further characterized in that it presents an infrared spectrum having peaks at 1664, 1617, 1583, 1510, 1460, 1405, 1343, 1291, 1214, 1193, 1131, 1094, 1044, 1002, 973, 957, 876, 831, 717, 755, 670, 576 and 544 ± 4 cm-1, as given in Figure .
The production of the novel minocycline chlorohydrate polymorph is based on the anti-solvent effect of carbon dioxide, after the gas mixing with solutions or suspensions of minocycline in organic solvents.
Carbon dioxide, which is miscible with most organic solvents, changes its properties after the process of dissolution, particularly the ability of solvating other molecules. This anti-solvent effect of carbon dioxide has been studied by many authors, mostly towards the micronization of active substances, but not to control its crystalline form.
Thereby, the process of producing crystalline thermo- resistant minocycline is characterized in that it comprises the mixture with carbon dioxide of a solution (or suspension) of minocycline chlorohydrate in an organic solvent .
Using ethanol. as an example, Figure 2 describes the thermodynamic fundament (phase equilibria) that supports the process mentioned in this invention.
As carbon dioxide dissolves in the organic solvent, pressure increases following the liquid-vapor equilibrium line (Figure 2) . When liquid carbon dioxide composition reaches approximately 0.6 molar fraction, a precipitate of minocycline chlorohydrate related to this invention is formed. The saturation composition of minocycline, to which corresponds the beginning of precipitation, is shown in Figure 2, for the particular case of a minocycline chlorohydrate solution, with an initial composition of 0.5% (mass percentage) in ethanol. Different initial compositions in minocycline, or the use of other organic solvents, require different carbon dioxide compositions in order to reach saturation.
In the absence of thermodynamic data of this nature, the necessary conditions to produce the polymorph to which this invention is related would be hardly achievable. This reason may explain the production of minocycline chlorohydrate only as amorphous, by other authors who also used methods involving the minocycline precipitation by carbon dioxide.
There are essentially two alternative ways for the mixing process which characterizes the production of minocycline chlorohydrate thermo-resistant . A) adding carbon dioxide to a precipitator containing the solution (or the suspension) ; B) adding the solution (or the suspension) to a precipitator containing carbon dioxide.
Example 1 illustrates the first alternative. In this exemplification, carbon dioxide is fed to a reactor containing minocycline chlorohydrate dissolved in an organic solvent. Example 2 describes a change-over of this method, which compasses the processing of a minocycline chlorohydrate suspension rather than a solution. In this last example, the minocycline chlorohydrate (purchased by Sigma Aldrich, Germany) was processed. The minocycline chlorohydrate is a mixture of several crystalline forms, as indicated by the corresponding thermogram shown in Figure 1. The suspension consists in a supersaturated solution of the initial product. In this case, the anti-solvent effect of carbon dioxide causes precipitation of the most stable crystalline form of dissolved chlorohydrate fraction - the thermo-resistant polymorph. Over time, the suspension is totally converted into a single polymorph - the most stable - which is the object of this invention. The use of suspensions, when compared with solutions, enables the achievement of relatively high yields of minocycline per unit of organic solvent and carbon dioxide.
Alternatively, and as the processing form B, the minocycline solution may be fed to a reactor containing pressurized carbon dioxide.
Carbon dioxide contained in the precipitator must be under such pressure and temperature conditions, so that C02 final composition in the mixture equals or exceeds the necessary value to cause the minocycline precipitation by anti- solvent effect. This process may be performed in a continuous or a semi-continuous mode. In the semi- continuous mode, the solution is fed into the precipitator in conditions that ensure the minocycline chlorohydrate precipitation and, simultaneously, the dissolution of the organic solvent in the C02-rich liquid phase. In this case, C02 feed flow rate must be enough to dissolve the flow-rate of the solvent contained in the solution. The solutes are loaded in the C02 pressurized precipitator, being separated from the out stream through a filter. This processed is exemplified in Example 3.
In the continuous mode operation, complete solvent dissolution in the C02 rich-liquid phase is not required. In this case, the liquid solution is continuously mixed with the CO2 in a static mixer, aiming to cause only the precipitation of the crystalline chlorohydrate minocycline. Here, both C02 and the organic solvent are separated from the chlorohydrate through spray-drying of the suspension previously formed on account of the two flows mixing. Minocycline chlorohydrate particles generated like this can be separated in cyclones or electrostatic precipitators, as Example 4 exemplifies .
The minocycline chlorohydrate polymorph, which this invention relates to, was also characterized in terms of its antibacterial activity. Microbiological studies were carried out against reference bacterial strains and multidrug resistant strains. The obtained results testified the antimicrobial activity preservation of the novel minocycline chlorohydrate polymorph, relatively to that of the product not processed with carbon dioxide.
Description of the figures
Figure 1 shows the comparison between the minocycline thermo-resistant thermogram produced by recrystallization with carbon dioxide (curve A) and the pre-processed minocycline thermogram (curve B) . The variable t refers to temperature values in °C, ΔΛ refers to the variation of enthalpy in arbitrary units and "endo" refers to the direction of the endothermic reaction.
Figure 2 illustrates the experimental observation of minocycline chlorohydrate precipitation in ethanol solutions, through pressure-composition diagram of ethanol- liquid phase carbon dioxide mixture, at different temperatures. Points corresponding to pressure and composition, where precipitation occurs, are marked by X. Lines were obtained using the equation of state described by Li et al. 2005.
Figure 3 represents the XRPD (X-Ray Powder Diffraction) pattern of minocycline thermo-resistant produced by recrystallization with carbon dioxide. Figure 4 represents the infrared spectra of minocycline thermo-resistant produced by recrystallization with carbon dioxide. Exemplification of the invention
Example 1
This example describes the production of minocycline chlorohydrate thermo-resistant polymorph after adding carbon dioxide to minocycline chlorohydrate solutions in ethanol .
1 g of minocycline chlorohydrate solution in ethanol (concentration of 5 mg/g) was added to a stainless steel reactor equipped with glass viewing windows. Carbon dioxide was added to the solution by means of a compressor. Dissolution of carbon dioxide in the solution induced the precipitation of minocycline chlorohydrate in the form of a thermo-resistant polymorph. The precipitation operation of minocycline chlorohydrate thermo-resistant polymorph occurred at different pressures, which were dependent on the reactor temperature, as described in Figure 2. The production of the precipitate was verified when the molar fraction of C02 (in the liquid phase) reached the value of 0.6, approximately, at all temperatures, namely at 35, 40 and 45 °C.
Example 2
This example describes the recrystallization of a mixture of crystalline forms of minocycline chlorohydrate (which characteristic thermogram is evidenced in Figure 1, curve B) into the thermo-resistant polymorph. This process consists in the suspension of minocycline chlorohydrates in a C02-rich liquid phase containing an organic solvent. Minocycline chlorohydrate (0.1 g) and ethanol (0.1 g) were added to a stainless steel reactor with a volume of 8 cm3, under stirring. The reactor was pressurized up to 20 MPa and 50 °C. The resulting suspension was kept under these conditions for 2 hours, while stirred with a magnetic stirrer at 200 rpm. Ethanol was removed together with C02 during de slow depressurization of the precipitator at 50 °C. The minocycline thermo-res.istant polymorph was collected from the inside of the reactor.
Example 3
This example demonstrates the production of minocycline chlorohydrate thermo-resistant polymorph through a method that operates in a semi-continuous mode. This process consists in the feeding of a solution of minocycline chlorohydrate in ethanol (5 mg/g) to a precipitator pressurized with C02. The mentioned solution was atomized inside the precipitator by means of a nozzle. This atomization was assisted by a C02 flow rate, which was co- depressurized along with the 'liquid through a nozzle (with a internal diameter and length of 150 μπι and 250 μπι, respectively) .
The solution flow rate was Ig/min. The C02 flow rate was 14g/min. Adding the solution to the precipitator pressurized with C02, causes the precipitation of the solutes as a result of the anti-solvent effect. Herein, the solvent remains in the C02-rich liquid phase, while the solutes precipitate and are separated from the C02-rich liquid phase by a filter placed at the precipitator exit. The experiment procedure is carried out by means of the continuous injection of solution and C02, which circulate through the precipitator (where precipitates are accumulated) . Pressure is kept through the discharge of the C02-rich liquid phase, which is regulated by a back- pressure" type controller. Approximately 100 g of solution were processed, for each tested pressure value. Then, the precipitator was depressurized and the minocycline chlorohydrate was collected from the filter and from the precipitator walls. In the three pressure values which were tested (10 MPa, 13 MPa and 20 MPa) the minocycline thermo- resistant polymorph was recovered. In all cases, the precipitator temperature was 50 °C.
Example 4
This example describes the production of minocycline chlorohydrate thermo-resistant polymorph through a method that operates in a continuous mode. Herein, a solution of minocycline chlorohydrate in ethanol (5 mg/g) is mixed to the carbon dioxide (in the conditions at which precipitation of the minocycline chlorohydrate thermo- resistant occurs), in a static mixer. In this example, the following conditions concerning the mixture were selected: pressure of 15 MPa, temperature of 45 °C, C02 flow rate of 20 g/min and solution flow rate of 1 g/min) . The mixer consisted in a tube with 5 mm of internal diameter and 10 cm of length (unfilled) . The mixture caused the precipitation of minocycline in the thermo-resistant chlorohydrate that stayed in suspension. This suspension was then subjected to atomization through a nozzle for the solvent drying and CO2 removal by spray-drying. In this example, the orifice nozzle presented a 150 μπ of internal diameter and 500 μπι of length. Drying operation took place in a precipitator at atmospheric pressure. Drying was aided by a current of hot air; in this example, nitrogen was used (30 L per min, approximately) at 70 °C. Precipitates were recovered in a cyclone and in an electrostatic precipitator. References
- Mendes Z, Antunes JR, Marto S, Heggie . Crystalline Minocycline Base and Processes for its Preparation. US Patent 20100286417; 2010-11-11.
- Hendriks JGE, van Horn JR, van der Mei HC, Busscher, HJ. Backgrounds of antibiotic-loaded bone cement and prosthesis-related infection. Biomaterials 2004;25:545-556.
- Huang V, Cheung CM, Kaatz GW, Rybak MJ. Evaluation of dalbavancin, tigecycline, minocycline, tetracycline, teicoplanin and vancomycin against community associated and multidrug-resistant hospital-associated meticillin- resistant Staphylococcus aureus. Int ' J Antimicrob Ag 2010; 35:25-29.
- Bishburg E, Bishburg K. Minocycline—an old drug for a new century: emphasis on methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. Int J Antimicrob Ag 1999; 34:395-401.
- Cui Q, Mihalko WM, Shields JS, Ries M, Saleh KJ. Antibiotic-Impregnated Cement Spacers for the Treatment of Infection Associated with Total Hip or Knee Arthroplasty. J Bone Joint Surg Am 2007;89:871-882.
- Pinheiro L, Bettencourt A, Duarte A, Bettencourt K, Almeida AJ, Castro M, Padrela L, Rodrigues MA, Matos HA. The Impact of Supercritical Fluids processing on Minocycline Antibacterial Activity. Proceedings of the 12th European Meeting on Supercritical Fluids (ISBN: 978-2905267-72-6) 2010, 6 pags. (ed. In CD-ROM).
- Tavares Cardoso MA, Geraldes V, Cabral JMS, Palavra AMF. Characterization of minocycline powder micronized by a supercritical antisolvent (SAS) process. J Supercrit Fluid 2008; 46:71-76.
- Jun Li, M. A. Rodrigues, H. A. Matos, E. Gomes de Azevedo VLE of Carbon Dioxide/Ethanol/Water: Applications to Volume Expansion Evaluation and Water Removal Efficiency Ind. Eng. Chem. Res., 2005, 44: 6751-6759.
- M Munto, N. Ventosa, S. Sala, J. Veciana, Solubility behaviors of ibuprofen and naproxen drugs in liquid "C02 - organic solvent" mixtures, The Journal of Supercritical Fluids 47 (2008) 147-153.
Date: December 17th, 2012

Claims

Crystalline minocycline chlorohydrate characterized in that it presents an X-ray diffraction pattern having peaks at 5.5, 9.6, 11.0, 13.5, 15.6, 15.8, 16.5, 16.8, 17.4, 18.3, 19.0, 19.2, 20.8, 22.0, 22.2 and 23.3 ±0.2° 2Θ.
Minocycline chlorohydrate, according to the previous claim, characterized in that it has an infrared spectrum having peaks at 1664, 1617, 1583, 1510, 1460, 1405, 1343, 1291, 1214, 1193, 1131, 1094, 1044, 1002, 973, 957, 876, 831, 717, 755, 670, 576 and 544
± 4 cm'
Minocycline chlorohydrate, according to the previous claims, characterized in that it has a melting temperature of 247 °C.
Minocycline chlorohydrate, according to the previous claims, characterized in that it is essentially a single polymorph.
Process of production of the minocycline chlorohydrate, defined in claims 1-4, characterized in that it comprises a mixture of carbon dioxide with organic solvents and minocycline chlorohydrates under pressure, temperature and composition conditions that exceeds the correspondent conditions to minocycline saturation in the mixture, determined by the phase equilibria.
-1-
6. Use of minocycline chlorohydrate defined in claims 1- 4, characterized in that the minocycline chlorohydrate is incorporated into the preparation of composite materials, prostheses, bone cements, implants, and controlled drug delivery formulations.
7. Use of minocycline chlorohydrate, according to claim 6, characterized in that the minocycline chlorohydrate is incorporated into the preparation of sterile pharmaceutical compositions or formulations, namely the ones sterilized by damp heat.
Date: December
PCT/PT2012/000051 2011-12-19 2012-12-17 Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide WO2013095169A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PT106063A PT106063B (en) 2011-12-19 2011-12-19 Thermorresistent crystalline minocycline produced by recrystallation with carbon dioxide
PT106063 2011-12-19

Publications (1)

Publication Number Publication Date
WO2013095169A1 true WO2013095169A1 (en) 2013-06-27

Family

ID=47563582

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PT2012/000051 WO2013095169A1 (en) 2011-12-19 2012-12-17 Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide

Country Status (2)

Country Link
PT (1) PT106063B (en)
WO (1) WO2013095169A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10351515B2 (en) 2015-02-13 2019-07-16 Hovione Scientia Limited Polymorphic forms of minocycline base and processes for their preparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4038315A (en) * 1972-05-11 1977-07-26 American Cyanamid Company Isolation and recovery of calcium chloride complex of 7-dimethylamino-6-dimethyl l-6-deoxytetracycline hydrochloride
PT103661A (en) 2007-02-23 2008-08-25 Hovione Farmaciencia S A Minocycine preparation process crystalline

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2561531B2 (en) * 1988-06-01 1996-12-11 日本化薬株式会社 Purification method of 7-dimethylamino-6-demethyl-6-deoxytetracycline
AU2003239463B2 (en) * 2002-02-01 2007-10-18 Pfizer Products Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions using pressure nozzles
US20070009564A1 (en) * 2005-06-22 2007-01-11 Mcclain James B Drug/polymer composite materials and methods of making the same
CN101693669B (en) * 2009-10-13 2012-08-08 浙江大学 Minocycline hydrochloride hydrate crystal forms and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4038315A (en) * 1972-05-11 1977-07-26 American Cyanamid Company Isolation and recovery of calcium chloride complex of 7-dimethylamino-6-dimethyl l-6-deoxytetracycline hydrochloride
PT103661A (en) 2007-02-23 2008-08-25 Hovione Farmaciencia S A Minocycine preparation process crystalline
WO2008102161A2 (en) 2007-02-23 2008-08-28 Hovione Inter Ltd. Crystalline minocycline base and processes for its preparation
US20100286417A1 (en) 2007-02-23 2010-11-11 Hovione Inter Limited Crystalline Minocycline Base and Processes for its Preparation

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BISHBURG E; BISHBURG K: "Minocycline-an old drug for a new century: emphasis on methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii", INT J ANTIMICROB AG, vol. 34, 1999, pages 395 - 401, XP026601916, DOI: doi:10.1016/j.ijantimicag.2009.06.021
CUI Q; MIHALKO WM; SHIELDS JS; RIES M; SALEH KJ: "Antibiotic-Impregnated Cement Spacers for the Treatment of Infection Associated with Total Hip or Knee Arthroplasty", J BONE JOINT SURG AM, vol. 89, 2007, pages 871 - 882
CUIXIANG SUN ET AL: "A Robust Platform for the Synthesis of New Tetracycline Antibiotics", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ACS PUBLICATIONS, US, vol. 130, 31 December 2008 (2008-12-31), pages 17913 - 17927, XP002604988, ISSN: 0002-7863, [retrieved on 20081203], DOI: 10.1021/JA806629E *
HENDRIKS JGE; VAN HORN JR; VAN DER MEI HC; BUSSCHER, HJ: "Backgrounds of antibiotic-loaded bone cement and prosthesis-related infection", BIOMATERIALS, vol. 25, 2004, pages 545 - 556, XP004469649, DOI: doi:10.1016/S0142-9612(03)00554-4
HUANG V; CHEUNG CM; KAATZ GW; RYBAK MJ: "Evaluation of dalbavancin, tigecycline, minocycline, tetracycline, teicoplanin and vancomycin against community associated and multidrug-resistant hospital-associated meticillin- resistant Staphylococcus aureus", INT J ANTIMICROB AG, vol. 35, 2010, pages 25 - 29
JUN LI; M. A. RODRIGUES; H. A. MATOS; E. GOMES DE AZEVEDO: "VLE of Carbon Dioxide/Ethanol/Water: Applications to Volume Expansion Evaluation and Water Removal Efficiency", IND. ENG. CHEM. RES., vol. 44, 2005, pages 6751 - 6759
KAMIHIRA M ET AL: "Removal of organic solvent from antibiotics with supercritical carbon dioxide", JOURNAL OF FERMENTATION TECHNOLOGY, ELSEVIER, JP, vol. 65, no. 1, 1 January 1987 (1987-01-01), pages 71 - 75, XP023543271, ISSN: 0385-6380, [retrieved on 19870101], DOI: 10.1016/0385-6380(87)90067-7 *
M MUNT6; N. VENTOSA; S. SALA; J. VECIANA: "Solubility behaviors of ibuprofen and naproxen drugs in liquid ''C02 - organic solvent'' mixtures", THE JOURNAL OF SUPERCRITICAL FLUIDS, vol. 47, 2008, pages 147 - 153, XP025868918, DOI: doi:10.1016/j.supflu.2008.07.013
PINHEIRO L; BETTENCOURT A; DUARTE A; BETTENCOURT K; ALMEIDA AJ; CASTRO M; PADRELA L; RODRIGUES MA; MATOS HA: "The Impact of Supercritical Fluids processing on Minocycline Antibacterial Activity", PROCEEDINGS OF THE 12TH EUROPEAN MEETING ON SUPERCRITICAL FLUIDS, 2010, pages 6
TAVARES CARDOSO MA; GERALDES V; CABRAL JMS; PALAVRA AMF: "Characterization of minocycline powder micronized by a supercritical antisolvent (SAS) process", J SUPERCRIT FLUID, vol. 46, 2008, pages 71 - 76, XP022688807, DOI: doi:10.1016/j.supflu.2008.02.018

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10351515B2 (en) 2015-02-13 2019-07-16 Hovione Scientia Limited Polymorphic forms of minocycline base and processes for their preparation
US10351516B2 (en) 2015-02-13 2019-07-16 Hovione Scientia Limited Polymorphic forms of minocycline base and processes for their preparation

Also Published As

Publication number Publication date
PT106063A (en) 2013-06-19
PT106063B (en) 2017-05-30

Similar Documents

Publication Publication Date Title
JP6815686B2 (en) 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
US10736896B2 (en) Substituted 5-fluoro-1H-pyrazolopyridines and their use
JP2019142882A (en) Crystalline minocycline base and processes for its preparation
JP5873923B2 (en) Bis (fluoroalkyl) -1,4-benzodiazepinone compound
Pasquali et al. Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics
KR101083498B1 (en) Substituted Tetracycline Compounds
KR101538175B1 (en) Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections
CN101711106B (en) Pharmaceutical use of substituted amides
JP4416652B2 (en) 3, 10 and 12a substituted tetracycline compounds
AU2002254991B2 (en) Tricyclic alkylhydroxamates, their preparation and their use as cell proliferation inhibitors
AU2017252640A1 (en) NLRP3 modulators
CN107207568A (en) immunomodulator
US9238622B2 (en) Crystal form I of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, preparing method and use thereof
JP2015518493A (en) Oxysterol analog OXY133 induces bone development and hedgehog signaling and inhibits adipogenesis
US8128909B2 (en) Preparation of sterile aqueous suspensions comprising micronised crystalline active ingredients for inhalation
CA2691987C (en) Antibacterial agents
JP5893651B2 (en) Pleuromutilin derivatives for the treatment of diseases mediated by microorganisms
JP2013525338A (en) Method for particle processing of active pharmaceutical ingredients
US6689767B2 (en) Triterpenes having antibacterial activity
ES2243458T3 (en) HYDROCLORIDE SALTS OF 5- (4- (2 - (- METIL-N- (2-PIRIDIL) AMINO) ETOXI) BENCIL) TIAZOLIDIN-2,4-DIONA.
KR0183027B1 (en) Pharmaceutical agents
JPWO2010150865A1 (en) crystal
JP5182956B2 (en) Tetracycline compounds with targeted therapeutic activity
CN107427491A (en) Therapeutic cyclic compound as immunomodulator
JP4686189B2 (en) Methods of using substituted tetracycline compounds to modulate RNA

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12816374

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12816374

Country of ref document: EP

Kind code of ref document: A1