ES2204306B1 - POLYMORPHIC FORMS OF DORZOLAMIDE CHLORHYDRATE, ITS OBTAINING AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

Polymorphic forms of dorzolamide hydrochloride, their preparation and pharmaceutical compositions containing them. A polymorphic form of dorzolamide hydrochloride substantially free of water and another containing a crystallization water molecule, which have been characterized by IR, DSC and DRX, are described. Said polymorphic forms can be obtained by crystallization in an organic solvent from the dorzolamide base by the addition of a solution of hydrogen chloride. The parameter that governs the obtaining of one polymorphic form or another is the concentration of water in the medium. Pharmaceutical compositions are useful for the treatment of ocular hypertension.

Description

Polymorphic forms of hydrochloride dorzolamide, its preparation and pharmaceutical compositions that they contain.

Field of the Invention

The invention relates to polymorphic forms of Dorzolamide hydrochloride, to procedures for obtaining it and to pharmaceutical compositions that contain them.

Background of the invention

Dorzolamide (D.C.I.) [(4S, 6S) -5,6-dihydro-4- (ethylamino) -6-methyl-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7,7-dioxide] is an aromatic sulfonamide substituted useful for the treatment of ocular hypertension.

The synthesis of dorzolamide, both in form racemic as its stereoisomers, and its salts pharmaceutically acceptable, such as hydrochloride dozolamide, is described in European patent EP 0 296 879. In said patent also describes the use of that compound in combination with a blocking agent β-adrenergic, for the treatment of intraocular hypertension Although the pharmaceutical form of administration of dorzolamide hydrochloride more widely used it is the ophthalmological solution, in said European patent are described other forms of administration, for example, forms of oral administration, such as tablets, capsules or equivalents, forms of nasal administration, such as sprays nasal, or parenteral administration forms, such as sterile injectable preparations, in which the factor of Polymorphism acquires particular relevance.

As is known, the different structures crystallines that a compound can present lead to a variation in its physicochemical parameters, by example, stability, dissolution rate, melting point, etc., which are directly related to the form crystalline polymorphic compounds. This variation in compound properties translates into a different bioavailability thereof, especially in those cases where that the active substance is administered in solid phase.

In addition, from the pharmaceutical point of view, it is very important to have unique crystalline forms to prepare pharmaceutical forms that meet the required specifications of pure pharmaceutical product. Obtaining crystalline forms unique solves the problems of lack of reproducibility and of Different bioavailability of pharmaceutical forms when polymorph mixtures are used.

There is, therefore, the need to have pure polymorphic forms of dorzolamide, as well as procedures that lead to its acquisition unequivocally and reproducible, for the preparation of pharmaceutical forms that contain a single polymorphic form and meet the requirements demanded by the pharmaceutical industry.

The solution provided herein The invention is based on the fact that the inventors have observed that, depending on the crystallization conditions of the hydrochloride of dorzolamide, different polymorphic forms are obtained that they differ in their infrared (IR) spectra, in their exotherms by differential scanning calorimetry (DSC) and in its X-ray diffractograms (DRX).

Therefore, in one aspect the invention is relates to new polymorphic forms of hydrochloride of dorzolamide, called Form A and Form B in this description, identified and characterized by IR, DRX and DSC.

In another aspect, the invention relates to procedures for preparation, unequivocally and reproducible, of said pure polymorphic forms of hydrochloride Dorzolamide

In another aspect, the invention relates to a pharmaceutical composition comprising a polymorphic form of Dorzolamide hydrochloride selected from Form A, Form B, and mixtures thereof, together with a pharmaceutically excipient acceptable.

In another aspect, the invention relates to the use of a polymorphic form of dorzolamide hydrochloride selected from Form A, Form B, and mixtures thereof, in the development of a suitable medication for the treatment of ocular hypertension

In another aspect, the invention relates to a method for treating an animal or an individual with intraocular hypertension, in need of treatment, which comprises applying to said animal or individual an amount therapeutically effective of a polymorphic form of hydrochloride of dorzolamide selected from Form A, Form B, and their mixtures

Brief description of the figures

Figure 1 is a graph showing the infrared (IR) absorbance spectrum of the polymorphic form of dorzolamide hydrochloride called Form A performed in potassium bromide tablet, in a spectrophotometer of Fourier transform infrared (FT-IR) Perkin-Elmer 1600. On the ordinate axis, represents the transmittance and on the abscissa axis the number of waves (cm -1).

Figure 2 is a graph showing the exotherm by differential scanning calorimetry (DSC) of the polymorphic form of dorzolamide hydrochloride called Form A. The ordinate axis represents the energy absorbed or transmitted per unit of time (mW) and in the abscissa axis the temperature (ºC) and the time
(minutes)

Figure 3 is a graph showing the X-ray powder diffraction spectrum (DRX) of the form polymorphic of dorzolamide hydrochloride called Form A, obtained at λ = 1.5406 angstrom, using a source of CuKα1, 40 kV and 30 mA radiation (equipment Debye-Scherrer INEL CPS-120). At ordinate axis pulses are represented and on the axis of abscissa the angle 2?

Figure 4 is a graph showing the infrared (IR) absorbance spectrum of the polymorphic form of dorzolamide hydrochloride called Form B performed in potassium bromide pill in a spectrophotometer FT-IR Perkin-Elmer 1600. On the shaft of ordinates the transmittance is represented and in the abscissa axis the number of waves (cm -1).

Figure 5 is a graph showing the differential scanning calorimetry exotherm (DSC) of the form polymorphic of dorzolamide hydrochloride called Form B. In the ordinate axis represents the absorbed or transmitted energy  per unit of time (mW) and on the abscissa axis the temperature (ºC) and time (minutes).

Figure 6 is a graph showing the X-ray powder diffraction spectrum (DRX) of the form polymorphic of dorzolamide hydrochloride called Form B, obtained at λ = 1.5406 angstrom, using a source of CuKα1, 40 kV and 30 mA radiation (equipment Debye-Scherrer INEL CPS-120). At ordered axis the impulses are represented and on the abscissa axis The angle 2?

Figure 7 shows the comparison between infrared absorbance (IR) spectra of the forms polymorphs of dorzolamide hydrochloride called Form A and Form B, made in potassium bromide tablet, in a FI-IR Perkin-Elmer spectrophotometer 1600. In the ordinate axis the transmittance is represented and in the abscissa axis the number of waves (cm -1).

Figure 8 shows the comparison between infrared absorbance (IR) spectra of the forms polymorphs of dorzolamide hydrochloride called Form A and Form B, made in suspension in Nújol, in a spectrophotometer FT-IR Perkin-Elmer 1600. On the shaft of ordinates the transmittance is represented and in the axis of abscissa the number of waves (cm -1).

Figure 9 is a graph showing the X-ray powder diffraction spectrum (DRX) of a mixture of the polymorphic forms of dorzolamide hydrochloride called Form A and Form B, obtained at λ = 1.5406 angstrom, using a CuK? 1, 40 kV and 30 mA radiation source (equipment Debye-Scherrer INEL CPS-120). At ordinate axis pulses are represented and on the axis of abscissa the angle 2?

Figure 10 is a graph showing the X-ray powder diffraction spectrum (DRX) of a mixture of the polymorphic forms of dorzolamide hydrochloride called Form A and Form B shown in Figure 9. On the axis of ordered impulses are represented and on the abscissa axis the angle 2?

Description of the invention

In a first aspect the invention provides polymorphic forms of dorzolamide hydrochloride, denominated, from now on, Form A and Form B, depending on which are substantially free of water or not.

Form A is a crystalline form substantially free of water (anhydrous) and solvent, as It has been proven by conventional techniques, such as gas chromatography and titration against Karl's reagent Fischer In the sense used in this description, the expression "substantially free of water and solvent" means that It has a water content of less than 0.5% by weight and a content in residual solvents less than 0.5% by weight.

Form A has been characterized by its spectrum of infrared absorption (IR), its exotherm by calorimetry scanning differential (DSC) and its X-ray diffractogram (DRX)

Form A exhibits an infrared (IR) spectrum in potassium bromide tablets substantially similar to shown in Figure 1, which has significant bands at approximately 3369, 3115, 3070, 3044, 2935, 2786, 2689, 2452, 1588, 1534, 1446, 1417, 1409, 1384, 1343, 1305, 1209, 1156, 1131, 1076, 1022, 992, 886, 741, 700, 643, 604, 567, 562, 508, 475 and 409 cm -1.

Registration of exotherm by calorimetry Scan Differential (DSC) of Form A has a maximum of 275 ° C approximately, which corresponds to the endothermic phenomenon of Fusion of Form A at high temperature (see Figure 2). He DSC exothermic recording was performed in a closed vessel, at a temperature between 25ºC and 320ºC, with a speed of 10ºC / min heating, in a Mettler Toledo Star System

Form A presents an X-ray diffractogram (DRX) substantially similar to that shown in Figure 3, with spikes characteristic at 9.6, 14.7, 20.2, 22.8 and 25.3 degrees 2 theta (2?), Using a CuK? 1 radiation source, 40 kV and 30 mA (Debye-Scherrer INEL equipment CPS-120).

More specifically, the DRX of Form A (see Figure 3) presents the characteristics listed in Table 1

TABLE 1 DRX Characteristics of the Form TO

Sequence 2 \ theta Distance (d) Relative intensity one 9,657 9.1514 100.00 2 13,932 6.3516 42.25 3 14,774 5.9912 29.86 4 16,980 5,2174 66.98 5 17,562 5,0458 11.47 6 18,150 4.8837 42.55 7 20,175 4.3980 52.23 8 20,679 4.2918 33.22 9 21,286 4,1708 12.89 10 21,790 4,0755 16.37 eleven 22,254 3.9915 10.51 12 22,869 3.8856 64.64 13 23,976 3,7086 29.64 14 25,369 3,5080 32.88 fifteen 25,886 3,4391 6.74 16 27,800 3,2065 52.89 17 28,169 3,1654 53.77 18 28,550 3.1240 19.41 19 29,126 3.0635 16.11 twenty 29,850 2.9908 18.51 twenty-one 30,224 2.9547 19.07 22 30,678 2.9120 6.52 2. 3 31,303 2,8552 3.36 24 32,575 2.7466 20.27 25 33,055 2,7078 6.18 26 34,120 2,6257 22.47 27 34,936 2,5662 22.95 28 35,590 2,5205 5.84 29 36,030 2,4907 10.89 30 37,557 2.3929 15.81 31 38,538 2,3342 3.92 32 39,431 2.2834 10.23

Form B is a crystalline form substantially free of solvent, as has been proven by conventional techniques, such as chromatography of gases, which is associated with a molecule of water of crystallization. Indeed, the Karl Fischer reagent titration puts manifestly a water percentage of 4.5% (w / w), which is equivalent to substantially to one mole of water per mole of hydrochloride dorzolamide, and, therefore, Form B is a monohydrate. At meaning used in this description, the expression "substantially solvent free" means that it has a residual solvent content less than 0.5% by weight.

Form B has been characterized by its spectrum of infrared absorption (IR), its exotherm by calorimetry scanning differential (DSC) and its X-ray diffractogram (DRX)

Form B exhibits an infrared (IR) spectrum in potassium bromide tablets substantially similar to shown in Figure 4, which has significant bands at approximately 3606, 3536, 3300, 3092, 2977, 1613, 1557, 1455, 1351, 1298, 1164, 1138, 1079, 1031, 990, 924, 887, 686, 615, 561, 541 and 530 cm -1.

The study of calorimetry exotherm Scan Differential (DSC) of Form B, which was performed in a vessel closed, at a temperature between 25ºC and 320ºC, with a heating rate of 10ºC / min, in a Mettler Toledo equipment  Star System, has three maxima (see Figure 5):

the first to Approximately 107 ° C, which is an endothermic transition, and it corresponds to the loss of a water molecule;

the second to Approximately 197 ° C, which is an exothermic transition, and is corresponds to a monotropic transition phenomenon solid-solid from Form B to Form A; Y

the third to 274 ° C approximately, corresponding to the endothermic phenomenon of Fusion of Form B at high temperature.

Form B presents an X-ray diffractogram (DRX) substantially similar to that shown in Figure 6, with spikes characteristic at 11.1, 19.1 and 23.4 degrees 2 theta (2?), using a CuKα1, 40 kV and 30 mA radiation source (Debye-Scherrer INEL team CPS-120).

More specifically, the DRX of Form B (see Figure 6) presents the characteristics listed in Table 2

TABLE 2 DRX Characteristics of the Form B

Sequence 2 \ theta Distance (d) Relative intensity one 8,959 9.8625 5.47 2 11,160 7,9221 50.65 3 13,263 6.6704 4.85 4 13,997 6.3223 10.76 5 14,982 5,9084 5.04 6 15,731 5,6287 6.92 7 16,376 5,4085 5.02 8 16,829 5.2639 8.13 9 18,082 4,9020 31.14 10 19,136 4.6342 23.55 eleven 19,510 4,5463 8.85 12 20,443 4.3409 9.82 13 20,711 4.2852 10.60 14 21,474 4.1348 4.72 fifteen 23,434 3.7932 100.00 16 24,989 3,5605 5.44 17 26,165 3.4031 11.75 18 26,597 3,3488 7.92 19 27,530 3,2374 13.18 twenty 28,072 3.1760 7.98 twenty-one 28,668 3,1114 5.18 22 29,889 2.9870 11.52 2. 3 30,566 2.9224 18.40 24 31,367 2,8495 4.23 25 32,278 2.7712 4.99 26 33,543 2,6695 6.90 27 34,738 2,5803 3.07 28 35,423 2.5320 3.84 29 36,290 2.4735 6.23 30 36,700 2.4468 4.11 31 37,371 2,4044 8.89 32 38,783 2,3200 5.87 33 39,735 2,2666 3.43

In view of previously analytical data mentioned, it can be affirmed that Form A and Form B are two different crystalline polymorphic forms of hydrochloride dorzolamide

From the crystalline point of view of the two isolated polymorphic forms, Form B (monohydrate) evolves by loss of the water molecule of crystallization that carries associated to Form A, regardless of the conditions of pressure and temperature This phenomenon is known as polymorphism. monotropic in which, regardless of the conditions and of irreversible form, the less stable polymorphic form evolves Towards the most stable.

IR studies, performed both in pill of potassium bromide as in suspension in numol, have provided equivalent results and allow to differentiate both forms polymorphs of dorzolamide hydrochloride.

Indeed, infrared spectroscopy (IR) is a very useful tool to differentiate between the two polymorphic forms A and B, even when there are mixtures of same, since very clear bands appear and characteristics of each of them in lengths in which none appears band of the other polymorphic form [see Figure 7 (IR, mixing Form A and Form B, in potassium bromide tablet) and Figure 8 (IR, mixture of Form A and Form B, suspended in number)]. So, for example, the band of 3370 cm -1, characteristic of the Form A, it clearly differs from the bands of 3606, 3536 and 330 cm -1 characteristics of Form B.

X-ray diffraction characterization in powder of polymorphic forms A and B is also significantly different, which highlights the existence of two different polymorphic forms. As it is known, X-ray studies are the best tool for differentiate between two polymorphic forms and determine the existence of mixtures of polymorphic forms, since each Polymorphic form has different diffractions and characteristics and, therefore, each of these can be identified unequivocally polymorphic forms and determine the existence of mixtures of same. In addition, this technique is quantitative and allows quantification the amount of each of the polymorphic forms present in a mixture of both polymorphic forms.

When comparing the DRX powders of Forms A and B (Figures 3 and 6, Tables 1 and 2) it is observed that there are differences in one of the polymorphic forms that fall in an area where no there are differences of the other polymorphic form. For example, a very intense diffraction in Form A corresponds to a Angle value 2 \ theta of 9.65, which does not match any diffraction of Form B which, in that area, has 2 diffractions, one at a value of the angle 2? of 8.95 and another at 11.16. Also, the diffraction at a value of the angle 2? Of 11.16 of Form B falls into an area where there is no diffraction of the Form A and therefore can be used to identify a mixture of polymorphic forms. In Figures 9 and 10 the DRX is shown in powder obtained for a mixture of the two polymorphic forms, Form A and Form B, in a case where Form A is a minority as opposed to Form B. In these Figures 9 and 10 the overlay of individual diffractograms and gets manifest the presence of Forms A and B.

Also, the 1 H NMR spectra and of 13 C of a mixture of both Forms A and B of hydrochloride dorzolamide, in solid state, show that they are forms polymorphs of the same chemical compound (data not shown). The purity of both polymorphic forms can be checked by techniques conventional, for example, by high-performance liquid chromatography resolution (HPLC).

The polymorphic forms of hydrochloride dorzolamide (Forms A and B) provided by this invention they represent a classic example of monotropic polymorphism, put that one of them, the least stable (Form B), becomes the more stable (Form A) regardless of the conditions of pressure and temperature Both polymorphic forms have been characterized using conventional techniques so that a subject matter expert can identify without problems each of them or a mixture thereof.

\hbox{y
B).}

In another aspect, the invention provides methods for obtaining, unequivocally and reproducibly, the polymorphic forms of dorzolamide hydrochloride provided by this invention (Forms A

 \ hbox {and
B).} 

Numerous tests carried out by the inventors have shown that, depending on the conditions of crystallization, each of the forms can be obtained polymorphic (A or B) dorzolamide hydrochloride form independent or a mixture of both.

In general, Forms A and B hydrochloride Dorzolamide can be obtained by crystallization in a solvent organic from dorzolamide base by adding a hydrogen chloride solution. Surprisingly, the parameter  that governs obtaining a polymorphic form or another is the water concentration in the medium. Also, surprisingly, it has found that Form A (anhydrous) is obtained under conditions of crystallization with excess water in the middle while the Form B (monohydrate) is obtained with low concentrations of water in the middle. Therefore, obtaining a polymorphic form or another, or a mixture of both, depends directly on the water concentration in the medium (critical process parameter of crystallization of one or another polymorphic form).

In general, the percentages indicated in This description refers to percentage by weight / weight (w / w) except otherwise indicated.

Form A, which is substantially free of water, can be obtained, for example, by crystallization from dorzolamide base in a reaction medium comprising acetate ethyl, optionally together with water, by adding the amount necessary of an aqueous or organic chloride solution of hydrogen, with the proviso that the final water content present in the reaction medium is different than 1% (w / w). The shape A can also be obtained by conventional techniques of recrystallization in different organic solvents, for example, methanol, isopropanol, n-propanol or acetate ethyl saturated with water, or in water, from the hydrochloride of Dorzolamide previously prepared.

More specifically, the invention provides a process for obtaining Form A of dorzolamide hydrochloride, method AI , which comprises reacting hydrogen chloride with a solution of dorzolamide base in ethyl acetate or in ethyl acetate and water, wherein the final water content in the reaction medium is different from 1% (w / w). To obtain Form A, the amount of water present in the medium may be greater than or less than 1% (w / w), but not 1% (w / w).

Procedure A.I comprises dissolving the Dorzolamide base in ethyl acetate or in a mixture of acetate ethyl and water. In a particular embodiment, the dorzolamide base it is dissolved in ethyl acetate (Examples 3 and 9). In other particular embodiment, the dorzolamide base is dissolved in acetate of water saturated ethyl (Examples 2, 5, 6, 7 and 8). Acetate ethyl is saturated with an amount of water of approximately 3.3%, which is the maximum amount of water that can dissolve in the ethyl acetate without a heterogeneous mixture.

Hydrogen chloride is added in solution Organic or aqueous In any case, the condition that the foral content in water in the middle of reaction, which comprises the solvent of the dorzolamide solution base and solvent of the hydrogen chloride solution, be other than 1% (w / w). In a particular embodiment, the chloride of hydrogen is added in the form of a chloride solution of hydrogen in an organic solvent, such as ethyl acetate (Example 2). In another particular embodiment, the chloride of hydrogen is added in the form of a solution of hydrogen chloride in water, for example, in a 35% aqueous solution (Examples 3, 5, 6, 7, 8, 9).

The amount of hydrogen chloride that is added must be at least equimolar with respect to the amount of dorzolamide initial free base, in order to ensure that the all of the free base dorzolamide initially present in the reaction medium is transformed into dorzolamide hydrochloride. When all of the dorzolamide base has become dorzolamide hydrochloride, the pH of dorzolamide solution It reaches a value of 3.5-3.6.

The invention provides an alternative method for obtaining Form A of dorzolamide hydrochloride, method A.II , which comprises crystallizing dorzolamide hydrochloride in a solvent selected from an alcohol substantially free of water and water.

In principle, any alcohol substantially Water-free can be used for the implementation of the procedure A.II. In the sense used in this description, the expression "alcohol substantially free of water" It means that it has a water content of less than 0.5% by weight. In a particular embodiment, said alcohol substantially Water-free is selected from methanol, isopropanol (Examples 10 and 11), n-propanol and mixtures thereof. In other particular embodiment, dorzolamide hydrochloride dissolves in water (Example 12).

The invention provides another alternative method for obtaining Form A of dorzolamide hydrochloride, method A.III , which comprises crystallizing dorzolamide hydrochloride in ethyl acetate saturated with water. The objective of procedure A.III is to dissolve dorzolamide hydrochloride in ethyl acetate saturated with water and then remove all water from the medium, distilling the necessary amount of solvent or replenishing it if necessary, so that at the end the amount of water in the medium is practically zero. Subsequently, the solution is allowed to cool to room temperature, kept under stirring and Form A (solid) is isolated by filtration (Example 4).

The invention also provides another alternative method for obtaining Form A of dorzolamide hydrochloride, method A.IV , which comprises subjecting Form B of dorzolamide hydrochloride to a heat treatment at a temperature between 15 ° C and 100 ° C, during a period of time of at least 4 hours, depending on the temperature (the higher the temperature the less the treatment time). In a particular embodiment, Form B is heated at 45 ° C, in an open crucible, for 60 days (Example 13) to obtain Form A of dorzolamide hydrochloride.

Form B dorzolamide hydrochloride, which it contains a molecule of water of crystallization in the structure crystalline, can be obtained by crystallization from the free amine (dorzolamide base) in ethyl acetate with a content in water of approximately 1%, by adding the amount necessary for a solution of hydrogen chloride, for example, a saturated solution of hydrogen chloride in acetate ethyl.

More specifically, the invention provides a process for obtaining Form B of dorzolamide hydrochloride, method BI , which comprises reacting hydrogen chloride with a solution of dorzolamide base in a mixture of ethyl acetate and water, wherein The final water content in the reaction medium is 1% (w / w). In a particular embodiment, the dorzolamide base is dissolved in a mixture containing ethyl acetate and 1% (w / w) of water (Example 14).

Hydrogen chloride is added in solution Organic or aqueous In any case, the condition that the final water content in the middle of reaction is 1% (w / w). In a particular embodiment, the chloride of hydrogen is added in the form of a chloride solution of hydrogen in an organic solvent, such as a solution saturated with hydrogen chloride in ethyl acetate (Example 14).

The amount of hydrogen chloride that is added must be at least equimolar with respect to the amount of dorzolamide initial free base.

The invention provides an alternative process for obtaining Form B of dorzolamide hydrochloride, method B.II , which comprises crystallizing dorzolamide hydrochloride in a mixture containing ethyl acetate and 1% (w / w) of water.

In another aspect, the invention provides a pharmaceutical composition comprising an amount therapeutically effective of a polymorphic form of hydrochloride of dorzolamide, selected from Form A, Form B, and its mixtures, together with a pharmaceutical carrier or excipient acceptable. In general, the pharmaceutical composition of the present invention will be adapted for administration via ophthalmologic, in the form of eye drops, although other ones are not ruled out Pharmaceutical forms of administration by other routes (oral, nasal, parenteral, etc.). A review of the different ways Pharmaceutical drug administration and its preparation It can be found in the book "Treaty of Galenic Pharmacy", by C. Faulí i Trillo, the Edition, 1993, Luzán 5, S.A. from Editions

As is known, dorzolamide is an inhibitor. of carbonic anhydrase so that the secretion of aqueous humor and, consequently, intraocular pressure. By therefore, in another aspect, the invention relates to the use of a polymorphic form of dorzolamide hydrochloride, selected between Form A, Form B and their mixtures, in the preparation of a suitable medication for the treatment of hypertension ocular.

In another aspect, the invention relates to a method for treating an animal or an individual with intraocular hypertension, in need of treatment, which comprises applying to said animal or individual an amount therapeutically effective of a polymorphic form of hydrochloride of dorzolamide selected from Form A, Form B and its mixtures

The following examples illustrate the invention and They should not be considered as limiting it. The example 1 describes obtaining dorzolamide hydrochloride, while Examples 2-13 describe obtaining the Form A of dorzolamide hydrochloride, and Example 14 describes the Obtaining Form B of dorzolamide hydrochloride.

I. Obtaining dorzolamide hydrochloride Example 1

Hydrochloride (4S, 6S) -5,6-dihydro-4- (ethylamino) -6-methyl-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7,7-dioxide:

one

it is prepared by dissolving 0.55g, (0.0017 mol) of dorzolamide base in 25 ml ethyl acetate, and Adjust the pH to 3.5-3.6 with 35% hydrochloric acid. He crude is concentrated to dryness, obtaining 0.62 g (95%) of dorzolamide hydrochloride, with a rotational power α = -8.3º.

II. Obtaining Form A of dorzolamide hydrochloride

Examples 2 to 13 describe obtaining the Form A. The studies by IR, DSC and DRX of the products obtained They confirmed that it was Form A.

Example 2

A solution of dorzolamide base (2 g), in water-saturated ethyl acetate (100 ml, 3.3% water), and Stir until completely dissolved. The pH of the solution is adjusted at 3.5-3.6 dripping on the prepared solution, the  sufficient amount of a saturated solution of chloride hydrogen in ethyl acetate, keeping the temperature between 20 and 25 ° C. Once the pH is adjusted, the resulting solution is vacuum distillate until all water is removed from the medium, replenishing the necessary organic solvent. It stays 30 minutes with gentle agitation The solid obtained is filtered under vacuum and washed with ethyl acetate (4 x 5 ml).

The wet cake is dried under vacuum until it reaches a constant weight keeping the temperature constant between 20 and 25 ° C Once dry, it is stored cold at a temperature below 4ºC and tightly closed.

Example 3

A solution of dorzolamide base is prepared (0.55 g, 0.0017 mol) in 25 ml of ethyl acetate, and adjust the pH at 3.5-3.6 dripping on the solution sufficient amount of 35% hydrochloric acid. The gross is concentrated to dryness The product is dried under vacuum to constant weight. A Once dry, it is stored cold at a temperature below 4ºC and tightly closed.

Example 4

10 g of dorzolamide hydrochloride are dissolved in 100 ml of ethyl acetate saturated with water. It heats up suspension at reflux and the amount of water needed is added to reach total dissolution. Once the entire product is dissolved, the ethyl acetate / water azeotrope is distilled until anhydrified completely the medium, replenishing the necessary amount of acetate of ethyl to recover the initial volume. It cools on approximately 2 hours to room temperature and 30 is maintained minutes with gentle agitation. The solid thus obtained is filtered at vacuum and wash with ethyl acetate (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold at a temperature below 4ºC and tightly closed.

Example 5

A solution of dorzolamide base (2 g), in water-saturated ethyl acetate (100 ml, 3.3% water) and Stir until completely dissolved. Then it heats up reach a constant temperature of 45 ° C. The pH of the solution at 3.5-3.6 dripping on the solution the sufficient amount of 35% hydrochloric acid, keeping constant temperature Once the pH is adjusted, it is distilled at empty until all the water is removed from the medium, replenishing the organic solvent needed. It is kept 30 minutes with stirring soft. The solid thus obtained is filtered under vacuum and washed with ethyl acetate (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry, it is stored cold to temperature below 4ºC and tightly closed.

Example 6

A solution of dorzolamide base (2 g), in water-saturated ethyl acetate (100 ml, 3.3% water) and Stir until completely dissolved. Then it heats up reach a constant temperature of 45 ° C. The pH of the solution at 3.5-3.6 dripping on the solution the sufficient amount of 35% hydrochloric acid, keeping constant temperature Once the pH is adjusted, 30 is maintained minutes with gentle agitation. The solid thus obtained is filtered at vacuum and wash with ethyl acetate (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold to temperature below 4ºC and tightly closed.

Example 7

It is prepared following the procedure of the Example 6, but adjusting the temperature to 5 ° C.

Example 8

It is prepared following the procedure of the Example 6, but adjusting the temperature between 20 and 25 ° C.

Example 9

A solution of dorzolamide base (2 g), in ethyl acetate (200 ml), stir until completely dissolved. The pH of the solution is adjusted to 3.5-3.6 dripping  on the solution the sufficient amount of hydrochloric acid 35%, keeping the temperature constant at 20-25 ° C Once the pH is adjusted, thirty is maintained  minutes with gentle agitation. The solid thus obtained is filtered at vacuum and wash with ethyl acetate (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold to temperature below 4ºC and tightly closed.

Example 10

10 g of dorzolamide hydrochloride are dissolved in 25 ml of methanol. The suspension is heated to reflux and add the amount of methanol needed to reach dissolution total. Once the entire product has dissolved, it cools in approximately 2 hours to room temperature and 30 is maintained minutes with gentle agitation. The solid thus obtained is filtered at vacuum and wash with methanol (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold to temperature below 4ºC and tightly closed.

Example 11

10 g of dorzolamide hydrochloride are dissolved in 25 ml of isopropanol. The suspension is heated to reflux and add the amount of isopropanol needed to reach total dissolution Once the entire product has dissolved, it cools in approximately 2 hours to room temperature and 30 is maintained minutes with gentle agitation. The solid thus obtained is filtered at vacuum and wash with isopropanol (4 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold to temperature below 4ºC and tightly closed.

Example 12

10 g of dorzolamide hydrochloride are dissolved in 25 ml of ultrapure water (TOC <15ppb). It heats up suspension at reflux and the amount of water needed is added to reach total dissolution. Once the entire product is dissolved, it cools in about 2 hours to room temperature and It is kept 30 minutes with gentle agitation. The solid thus obtained filtered under vacuum and washed with water (2 x 5 ml).

The wet cake is dried under vacuum until it reaches constant weight keeping the temperature constant between 20-25 ° C Once dry it is stored cold to temperature below 4ºC and tightly closed.

Example 13

The polymorphic form of hydrochloride (4S, 6S) -5,6-dihydro-4- (ethylamino) -6-methyl-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7,7-monohydrate dioxide (Form B) is subjected to a temperature of 45 ° C, in open crucible for 60 days to give the hydrochloride of (4S, 6S) -5,6-dihydro-4- (ethylamino) -6-methyl-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7,7-dioxide (Form A).

III. Obtaining Form B dorzolamide hydrochloride

Example 14 describes obtaining Form B of dorzolamide hydrochloride.

Example 14

A solution of dorzolamide base (2 g), in ethyl acetate with a percentage of water of 1% (100ml, 1% of water), stir until completely dissolved. The pH of the solution fits 3.5-3.6 dripping on solution previously prepared, the sufficient amount of solution saturated with hydrogen chloride in ethyl acetate, keeping the temperature between 20 and 25 ° C. Once the pH is adjusted, it Keep with gentle agitation. The solid thus obtained is filtered at vacuum and wash with ethyl acetate (4 x 5 ml).

The wet cake is dried at a constant temperature and below 20ºC, until constant weight is reached. Once dry it Store cold at a temperature below 4ºC and tightly closed.

Studies by IR, DSC and DRX of the product obtained confirmed that it was Form B.

Claims (14)

1. A polymorphic form of (4S, 6S) -5,6-dihydro-4- (ethylamino) -6-methyl-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7,7-dioxide hydrochloride monohydrate, called Form B, characterized in that:

exhibits a infrared (IR) spectrum in potassium bromide tablets substantially similar to that shown in Figure 4, which has bands significant at approximately 3606, 3536, 330, 3092, 2977, 1613, 1557, 1455, 1351, 1298, 1164, 1138, 1079, 1031, 990, 924, 887, 686, 615, 561, 541 and 530 cm -1;

the exotherm for differential scanning calorimetry (DSC) has three maximums, one at approximately 107 ° C, another at approximately 197 ° C and the third at 274 ° C approximately; Y

present a X-ray diffractogram (DRX) substantially similar to that shown in Figure 6, with characteristic peaks at 11.1, 19.1 and 23.4 degrees 2 theta (2 \ theta).

2. A procedure to obtain the Form Dorzolamide hydrochloride B, which comprises reacting hydrogen chloride with a solution of dorzolamide base in acetate of ethyl and water, where the final water content in the middle of reaction is 1% (w / w). 3. Method according to claim 2, in the that hydrogen chloride is added in the form of a solution Organic or aqueous 4. Method according to claim 3, in the that hydrogen chloride is added in the form of a solution of hydrogen chloride in ethyl acetate. 5. A procedure to obtain the Form B of dorzolamide hydrochloride, which comprises crystallizing the Dorzolamide hydrochloride in a mixture containing acetate ethyl and 1% (w / w) of water. 6. A procedure to obtain the Form A of dorzolamide hydrochloride, which comprises reacting hydrogen chloride, dissolved in ethyl acetate, with a solution of dorzolamide base in a mixture of ethyl acetate and water, in where the final water content in the reaction medium is different from 1% (w / w). 7. A procedure to obtain the Form A of dorzolamide hydrochloride, which comprises crystallizing the Dorzolamide hydrochloride in a solvent selected from a alcohol substantially free of water and water. 8. Method according to claim 7, in the that said substantially water-free alcohol is selected from methanol, isopropanol, n-propanol and mixtures thereof. 9. Method according to claim 7, in the that dorzolamide hydrochloride crystallizes in water. 10. A procedure to obtain the Form A of dorzolamide hydrochloride, which comprises crystallizing the dorzolamide hydrochloride in ethyl acetate saturated with Water. 11. A procedure to obtain the Form A of dorzolamide hydrochloride, which comprises subjecting the Form B dorzolamide hydrochloride at a heat treatment at a temperature between 15ºC and 100ºC, during a period of time of at least 4 hours. 12. A pharmaceutical composition comprising a therapeutically effective amount of polymorphic form B of the Dorzolamide hydrochloride according to claim 1, together with a pharmaceutically acceptable carrier or excipient. 13. Pharmaceutical composition according to claim 12, adapted for administration via route ophthalmologic, in the form of eye drops. 14. Use of polymorphic form B of Dorzolamide hydrochloride according to claim 1, in the development of a suitable medication for the treatment of ocular hypertension