MXPA03005888A

MXPA03005888A - Amlodipine free base.

Info

Publication number: MXPA03005888A
Application number: MXPA03005888A
Authority: MX
Inventors: Keltjens Rolf
Original assignee: Pfizer Ltd
Priority date: 2000-12-29
Filing date: 2001-12-31
Publication date: 2005-04-19
Also published as: AU2001294354A1; WO2002053135A1; EP1345901A2; BR0116558A; WO2002053535A3; CZ20031779A3; CA2433366C; ES2277960T3; DE60125981T2; AU2001294354A8; DE60125981D1; DE20116723U1; CA2433366A1; WO2002053535A2

Abstract

Amlodipine free base can be formulated into a convenient oral dosage form, especially a tablet, without excessive stickiness or tablet punch residue. The amlodipine free base can be crystalline Form I or a novel Form II. Methods of making and using the amlodipine free base are set forth.

Description

AMLODIPINE FREE BASE FIELD OF THE INVENTION The present invention concerns the free base of amlodipine, to compositions comprising the free base of amlodipine and to the use of the free base of amlodipine in therapy.

BACKGROUND OF THE INVENTION EP 089 167 and the corresponding EUA 4,572,909 disclose a class of substituted dihydropyridine derivatives which are useful calcium channel blockers. These patents identified that one of the most preferred compounds is 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropy idine. This compound, which is currently commonly known as amlodipine, has the following formula: While amlodipine is generally shown as a free base and as a pharmaceutically acceptable acid addition salt, the examples of amlodipine are all made as amlodipine maleate; for example, examples 9, 11, 12, and 22 or EP 089 167. The maleate salt is identified as the most preferred acid addition salt. Surprisingly, the free base of amlodipine is not characterized. The examples appear to describe the formation of the free base but only as a solution / suspension (example 11) or as a residue remaining after evaporation of the solvent (examples 12 and 22). Only the maleate salt of amlodipine is described as a precipitate from a solution (examples 12 and 22). Subsequently, EP 244 944 and the corresponding EUA 4,879,303 were published directed to the besylate salt (or benzenesulfonate) of amlodipine. The besylate salt is established to provide certain advantages over known salts including amlodipine maleate. Several salts of amlodipine were compared for their water solubility, stability, non-igroscopicity, and processability for tablet formation. The free base of amlodipine was included in the processability tests that involved measuring the amounts of amlodipine remaining in the tablet punch after making the tablets. Amlodipine-free base tablets were reported to leave an average of 2.02 μg of amlodipine / cm2 per tablet on the punch. It was reported that the amlodipine besilate tablets left an average of 1.17 g of amlodipine / cm2 per tablet. Thus, the free base compositions suffered from excessive adherence to the tacking punch and was not as adequate in the preparation of the solid dosage forms for oral administration. The besiloate salt of amlodipine is described in Examples 1 and 5 below, as it was made from the free base of amlodipine in suspension, although no method of how the free base was prepared is disclosed. D. M. McDaid and P. B. Deasy in Int. J. Of Pharmaceutics 133, 71-83 (1996), suggests the use of the free base of amlodipine in a transdermal pharmaceutical product such as a patch. The free base of amlodipine in the solid state was prepared in the previous article, its structure was confirmed by NMR, and was characterized by a melting point of 144 ° C and aqueous solubility of 77.4 mg / 1. The solid base amlodipine was prepared by neutralization of a solution of amlodipine besylate with sodium hydroxide. In a first process, the besylate was dissolved in methanol at 20 ° C, an aqueous solution of sodium hydroxide was added and the base was extracted from the mixture by means of diethyl ether, which was then evaporated. It was observed that this process, as described, is irreproducible when the diethyl ether is miscible with the reaction mixture. In a second process, an aqueous solution of the besylate was treated at 50 ° C with a solution of sodium hydroxide and the base crystallized after cooling to 4 ° C. It would be desirable to have an oral dosage form of amlodipine based on the free base of amlodipine. Such a dosage form would preferably be equivalent to the acid addition salt forms of amlodipine, especially the commercial amlodipine besylate salt, and would not suffer from significant stability or manufacturing problems. In addition, it would be desirable to provide a direct method for forming the amlodipine-free base that can allow isolation, inter alia, by filtration.

SUMMARY OF THE INVENTION The present invention is based on the study of the free base of amlodipine and the discovery of several physical properties thereof. From an embodiment of these properties, the present invention provides a pharmaceutical dosage form of the amlodipine free base useful, especially a tablet, a new crystalline form of amlodipine-free base, an amlodipine free base population in the form of particles that be useful when making a tablet, and a process to form more economically, the free base of amlodipine. Accordingly, a first aspect of the present invention concerns a pharmaceutical tablet composition comprising an effective amount of free amlodipine base and at least one pharmaceutically acceptable excipient; wherein the tablet exhibits little punch residue, as defined below. Preferably the tablet leaves an average residue on the tabletting punch of 0.7 g-cm- per tablet or less. Another aspect of the present invention concerns form II of the free base of crystalline amlodipine. This new crystalline form of amlodipine is also suitable for use as the pharmaceutical active agent. Another aspect of the present invention concerns a free base amlodipine population in particle form having an average particle size of at least 100 microns. Preferably the particles are crystals and the average particle size is 150 to 350 microns. Such a population in the form of particles is useful in the formation of a tablet composition. A further aspect of the invention pertains to a method of treating or preventing hypertension, angina, or congestive heart failure, which comprises administering an effective amount of amlodipine-free base to a patient in need thereof. Preferably the free base of amlodipine is administered in the aforementioned tablet form. Yet a further aspect of the present invention concerns a process comprising deprotecting an N-protected amlodipine with a deprotecting agent to form the free base of amlodipine; precipitate the free base of amlodipine from a solution; and isolating the free base of precipitated amlodipine as a solid state. The solution form from which the free amlodipine base precipitates may be the solution resulting from the deprotecting step or a different solution; that is, in an extraction solvent. Another aspect of the present invention concerns a process for purifying the free base of amlodipine, which comprises: crystallizing the free base of amlodipine from a non-aqueous solvent. Selling the crystallization produces amlodipine free base crystals having an average particle size of 150 to 350 microns.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a powder X-ray diffractogram for the free base of amlodipine (Form I) of reference example 3. Figure 2 shows an IR spectrum of the free base of crystalline amlodipine (Form I) of Example 1. Figure 3 shows a DSC curve of the crystalline amlodipine free base (Form I) of Example 1. Figure 4 shows an IR spectrum of the free base of crystalline amlodipine (Form I) of Example 4a. Figure 5 shows a DSC curve of the crystalline amlodipine free base (Form I) of example 4a. Figure 6 shows an IR spectrum of the crystalline amlodipine free base (Form II) of example 5a. Figure 7 shows a DSC curve of the free base of crystalline amlodipine (Form II) of example 5a. Figure 8 shows a powder X-ray diffractogram of the crystalline amlodipine free base (Form II) of example 5b.

DETAILED DESCRIPTION OF THE INVENTION An amlodipine-free base tablet according to the present invention is preferably a tablet with a low punch residue. A "low punch residue", as used herein, means that the average amount of amlodipine left on the tabletting punch is not more than 1 μg / cm2 per tablet based on a 20 mm round flat punch with a force of compression of 15 kilo-newtons. Preferably, the tablet has an average punch residue of 0.7 μg / cm2 per tablet, more preferably 0.6 g / cm2 per tablet. The amount of amlodipine residue can be measured by the process described in EP 244 944. In general the method involves washing the punch after the exit of 50, 100, 150, 200, 250 and 300 tablets, using methanol and an ultrasonic bath . The amount of amlodipine in the samples is measured by UV rays and the total amount of amlodipine extracted from both punches, the superior and the inferior, is plotted against the amount of tablets made. An average value for the amlodipine residue (adhesion) is calculated from the slope of the regression line by forcing the intersection of "" and "of the line to zero.The tablet comprises an effective amount of free amlodipine base and at least A "pharmaceutically acceptable excipient" An "excipient" as used herein means any inactive, pharmaceutically acceptable component of the composition As is well known in the art, excipients include diluents, binders, lubricants, disintegrants, colorants, antioxidants / preservatives, pH adjusters, etc. The excipients are selected based on the desired physical aspects of the final form: for example, obtain a tablet with the desired hardness and friability, which is quickly dispersible and easily swallowed, etc. The rate of release desired of the active substance from the composition after its ingestion also plays a role in the selection of For example, the preparation can, if desired, be designed to give slow release of the free base of amlodipine.

Suitable excipients for use in this invention include: a diluent such as calcium biphosphate, lactose, mannitol, etc. - a binder such as microcrystalline cellulose or a modified cellulose, povidone, etc. - a disintegrant such as sodium starch glycolate, crospovidone - a lubricant such as magnesium stearate, sodium stearyl fumarate, talc - a dye, taste masking agent, etc. The tablets of the invention preferably do not require any anti-adherent agent such as talc. The composition of the tablet preferably comprises a calcium phosphate excipient and / or microcrystalline cellulose and more preferably both a calcium phosphate and microcrystalline cellulose. An example of an excipient calcium phosphate is anhydrous calcium biphosphate. In addition, the tablet may contain other conventional excipients such as binders, lubricants, disintegrants, colorants, preservatives, etc. The free base of amlodipine can be of any form including crystalline form I, crystalline or amorphous form II. Form I is characterized by a powder X-ray diffraction pattern, as shown in Figure 1, an IR spectrum as shown in Figures 2 or 4 and by a unique endothermic fusion on the DSC curve with start at approximately 140 ° C as shown in Figures 3 and 5. This form corresponds to the material described by McDaid and Deasy. Form II is a new form and is characterized by a distinctive powder X-ray diffraction pattern as shown in Figure 8, an IR spectrum as shown in Figure 6 and by means of a DSC curve, characterized by an endothermic or endo / exothermic transition at a temperature of about 100 ° C and an endothermic melting at about 140 ° C as shown in Figure 7. Although it is possible to convert Form II into Form I by applying sufficiently high temperatures, Generally higher than 100 ° C, Form II is generally stable at ambient conditions and even at moderately elevated temperatures. For example, Form II is stable after 1 month of rest at 60 ° C. Therefore, Form II is thus useful in the preparation of the final pharmaceutical forms. The free base of amlodipine in the tablet of the present invention can be of a single type or can be a mixture. For example, a mixture of crystalline Forms I and II.

To reduce the adhesion of the tablets, it is generally desired to control the size of the free base of amlodipine and / or the excipients used. Specifically, it is preferred that the free base of amlodipine be incorporated into the tablet composition in the form of particles having an average particle size of at least 100 microns, preferably 150 to 350 microns, more preferably 200 to 300 microns. The particulate materials are generally free base crystals of amlodipine, although non-crystalline forms are also included. The moisture in the tablets is preferably limited in order to reduce the adhesion. The preferred excipients are calcium phosphate and microcrystalline cellulose, as described above. The amount of the free base of amlodipine is not particularly limited and includes any amount that provides a pharmaceutical effect. In particular, the free base of amlodipine can be used to treat or prevent congestive heart failure due to hypertension or angina by administering an effective amount to a patient in need of it. The specific form of angina is not particularly limited and specifically includes chronic stable chest angina and vasospastic angina (Prinzmetal angina). The "patients" that are intended to be treated include human and non-human animals, especially human and non-human mammals. Generally the amount of free base of amlodipine in a unit dose is from 1 to 100 mg, more typically from 1 to 25 mg, and preferably about 1, 1.25, 2.5, 5 or 10 mg. In relative terms, the amount of free base of amlodipine in the composition may be preferably between 2 and 10.

? · The free base of amlodipine used in the tablet of the present invention can be made by any conventional means. Preferably, the free base is formed and isolated by means of a process comprising deprotecting an N-protected amlodipine with a deprotecting agent to form the free base of amlodipine; precipitate the free base of amlodipine from a solution; and isolating the free base of precipitated amlodipine as a solid state. An N-protected amlodipine is an amlodipine compound wherein the terminal amino group is protected as shown in formula (2): (2) wherein N-prot means an amino group protected by means of a fragmentable protecting group, such as by means of a benzyl group or a triflyl group, or concealed in a group convertible to amino group, such as a phthalimido group or an azido group . In a preferred embodiment, the protected amlodipine is an amlodipine compound protected with phthalimido of the formula (2a): This protected amlodipine is frequently mentioned in the following as phthalodipine. According to the invention, the free base of amlodipine can be prepared in the solid state by means of a suitable preparation of the reaction mixture obtained after the last synthetic step leading to the amlodipine; that is, the step comprising the deprotection of the amlodipine precursor of the above formula (2). Suitable de-protecting agents are well known in the art and the selection thereof is dependent on the protecting group that is employed. The free base of amlodipine is obtained without the need to form, and particularly to isolate, an amlodipine salt. The process is characterized in that no agent or acid medium is used for deprotection or for processing purposes; that is, the free base of amlodipine formed by deprotection is the free base that precipitates without the intermediate step of forming an amlodipine salt. The process of the present invention requires "precipitating" the free base of amlodipine from a solution. Precipitation is a well-known phenomenon by means of which a solid phase is separated from a solution. It is an advantage of a precitation that the solid phase comprising the desired product can be separated from the liquid phase comprising the solvent and soluble co-products; that is, collateral products or impurities. Thus, precipitation is also a tool to get rid of at least some product impurities. This is not possible if a solid product is obtained from a solution by simple evaporation of the solvent. Thus, for purposes of the present invention, precipitation does not include evaporating all the solvent in a solution to leave a residue. The precipitation is preferably a crystallization, although it is not limited thereto. Precipitation that involves reducing the temperature of the solution generally leads to crystallization while precipitation involving a change in pH can lead to a more classical precipitation of the solid either in crystalline or non-crystalline form. The solution can be formed directly by means of the deprotection step or it can be a different solution, such as one formed by means of an extraction process. The solution may be aqueous, non-aqueous, or a mixture of solvents. In general, an aqueous solvent leads to the formation of small particle sizes. The purification step described below can be used to obtain free base amlodipine particles of a size larger than desired. The isolation of the solid form of the precipitated amlodipine-free base can be by any technique known or suitable for separating a solid phase from a liquid phase, i.e., a solvent or a solution. Preferably the isolation stage uses filtration.

The invention will be described with respect to its preferred embodiment wherein the phthalodipine of formula (2a) is used as the N-protected amlodipine compound. In accordance with EP 89167, phtalodipine is deprotected either by ethanolic methylamine, ethanolic hydrazine hydrate or by mixing KOH in water / tetrahydrofuran. These techniques are suitable for the process of our invention, however they are not very economical. In a more advantageous embodiment, the deprotection is carried out by means of the treatment of phthalodipine with an aqueous solution of methylamine. It is the advantage of the aqueous solution of methylamine that the free base of amlodipine is simply separated from the reaction mixture and can be simply isolated in the solid state by filtration. The co-product of the deprotection reaction (N-methylphthalamide) remains in the aqueous solution. The reaction with aqueous methylamine solution can be carried out at a temperature from the ambient to about 60 ° C, preferably at 30-50 ° C. The course of the reaction can be monitored by means of any suitable analytical technique allowing the separation of the initial material and the product, for example, by HPLC. The product can be separated by filtration at 5-25 ° C, preferably at room temperature. In an alternative embodiment, the reaction mixture comprising the free base of amlodipine can be made by extraction of the amlodipine from the aqueous alkaline solution by means of an organic solvent immiscible with water, for example, toluene. The extraction temperature is essentially the environment. The concentration of the extraction solution allows the precipitation of the free base of crude amlodipine in the solid state. A counter-solvent (eg, hexane) may be added to the extraction solution, particularly the concentrated solution, to facilitate the precipitation of the free base of amlodipine, in the solid state. The free base of crude amlodipine can be further purified by various techniques. It will be noted that the meaning of "crude solid amlodipine" is not limited to only the free base of solid amlodipine prepared by means of the above method of our invention but encompasses any solid amlodipine base that has been further purified. "Purification" is used herein in a broad sense to include improving the size of the crystal, ie, removing small crystals in favor of the larger crystals, as well as reducing the level of contaminants in the free base of amlodipine. In particular, precipitation from aqueous solutions generally produces the free base of amlodipine as fine particles. Purification by means of a crystallization purification step can be used to obtain crystals of the amlodipine free base having a larger, more desirable particle size. In a first purification method, the free base of amlodipine is crystallized from a solution based on a suitable non-aqueous solvent, sometimes referred to hereafter as a "purification solvent". Preferably, the solution of amlodipine in the solvent is carried out under elevated temperature which can still comprise the boiling temperature of the purification solvent. If desired, the obtained solution can be further purified by means of conventional adsorption techniques, for example, by treatment with activated carbon or silica gel, before crystallization. Crystallization from solution can be carried out in several ways: by forced or spontaneous cooling of the free base solution of amlodipine by the addition of an at least partially miscible sub-solvent to a free base solution of amlodipine (under agitation or under diffusion), optionally in combination with forced or spontaneous cooling by evaporation of a part of the solvent, optionally in combination with any of the preceding techniques. Suitable solvents include aliphatic C 1 -C 4 alcohols such as methanol, or ethanol, chlorinated C 1 -C 4 hydrocarbons such as chloroform, alkyl esters of aliphatic acids such as ethyl acetate, nitriles of aliphatic acids such as acetonitrile, aromatic hydrocarbons such as toluene, C1-C6 ketones such as acetone, and mixtures thereof. Suitable counter solvents can be either more polar than the solvent; an example is water, or be less polar than the solvent; An example is hexane or heptane.

In another purification method, the free base of crude amlodipine is dissolved in a slightly miscible or immiscible purification solvent in suitable water, for example toluene, the toluene solution is extracted by means of an acidic aqueous solution to provide an aqueous solution of salt of amlodipine, which is then neutralized by means of a base, for example an alkali or an amine. The amlodipine base formed can be precipitated from the aqueous solution and can be separated, or it can be retro-extracted in an organic solvent immiscible or slightly miscible with water which is then cooled, concentrated or mixed with a counter-solvent, with which the free base precipitates of purified amlodipine from the solution. The nature of the acid could preferably be selected so that the amlodipine salt formed is soluble in water. The right acid is hydrochloric acid. The free base of amlodipine in a solid form can also be prepared by freeze drying a solution thereof, for example, a solution in ethanol-water (2: 1). By means of any of the above purification or production methods, except when working under the conditions that will be discussed below, the free base of amlodipine was obtained in crystalline Form I. Under certain conditions, a new polymorphic form of the free base of amlodipine in the solid state (Form II) can be prepared from the solutions of the free base of amlodipine. In general, conditions require crystallization to begin at low temperatures and typically with rapid cooling to prevent the formation of the core of Form I. For example, Form II is formed if the solution of the free base of amlodipine is a non-aqueous solvent , for example, toluene, is treated by a counter solvent, for example, hexane, cyclohexane or heptane, at temperatures below 5 ° C. The "free base solution of amlodipine in a non-aqueous solvent" includes the crude solution, for example, toluene solution, obtained from the deprotection step. Adding a solvent-based solution involves placing a counter-solvent in cold-free or cool amlodipine-free base solution or applying the solution of the free base of amlodipine to a cold counter-solvent. Generally, the use of a backsolvent allows to use a higher crystallization temperature when forming Form II. In an alternative process, Form II can be formed by means of a precipitation after forced cooling of a free base solution of amlodipine in a suitable crystallization solvent, for example ethyl acetate, where precipitation begins at the temperature lower than 5 ° C, more preferably lower than -5 ° C, and more usually at -10 ° C or lower including -20 ° C and lower. It will be noted that the free base of amlodipine, particularly Form II of the free base of crystalline amlodipine and the free base of purified amlodipine described above, can also be used as an intermediate in the production of the acid addition salts of amlodipine. In an advantageous embodiment, the amlodipine base purified by methods of the invention is reacted with a pharmaceutically acceptable acid to form an amlodipine salt exhibiting a desired degree of purity, for example, pharmaceutical purity, without a need for further purification. The amlodipine salts can be prepared, for example, by treating the solution or suspension of amlodipine base in a suitable solvent with an equivalent amount of an acid and isolating the salt formed from the reaction mixture. The amlodipine salts preparable by this method preferably includes, but is not limited to, salts with pharmaceutically acceptable acids; examples are maleate, fumarate, hydrogen maleate, besylate, monohydrated besylate, besylate dihydrate, hydrochloride, mesylate, mesylate monohydrate, hydrobromide, citrate and amlodipine tartrate. The process suitable for making free base tablets of amlodipine can comprise any conventional process. The compositions of this invention can be formulated by means of conventional mixing methods such as blending, filling and compression, by means of wet granulation, dry granulation or direct compression. The following process is the most advantageous and one preferred and can be applied to the composition for tablets of the invention on an industrial scale. Although the present invention is directed primarily to tablets, a capsule dosage form can also be prepared from the free base of amlodipine. The capsule compositions may comprise essentially the same excipients as the tablet compositions. An inert carrier is microcrystalline cellulose without calcium phosphate. The amlodipine free base can also be used in medical applications in combination with other hypertensive and / or antiangic agents, for example, with ACE inhibitors such as benazepril. The combination may be in a single combination preparation form, for example a capsule containing free base of amlodipine and benazepril hydrochloride, or by separate administration of drugs containing the above agents. The free base of amlodipine can also be used in combination with various cholesterol-lowering agents such as lovastatin, simvastatin or atorvastatin. The free base of amlodipine can be used in the management of the following disorders: Hypertension Chronic stable chest angina Vasotapastic angina (Prinzmetal angina) Congestive heart failure These disorders will be referred to hereinafter as "Disorders" '. Accordingly, the present invention further provides a method for treating and / or preventing any one or more of the Disorders by administering an effective and / or prophylactic amount of free amlodipine base in a composition of the invention to a patient in need thereof. An effective amount is known in the art. For example, in humans, an effective amount is typically between 1 and 100 mg of amlodipine-free base. A unit dose as previously described is usually taken from 1 to 3 times daily, preferably once a day. In practice, the physician will determine the current dosage and the administration regimen that will be most suitable for the individual patient.

The present invention also provides the use of the composition of the invention in the manufacture of a medicament for treating and / or preventing any one or more of the Disorders. The following examples illustrate the invention but were not constructed as limiting the invention itself. Reference Example 1, based on McDaid and Deasy 1.15 g of amlodipine besylate was dissolved in 250 ml of water at 50 ° C- 55 ° C. A solution of 1 M NaOH (2.2 ml) was added. The mixture was set at 3 ° C - 5 ° C and stirred at this temperature for 1 hour. The solid was separated by filtration and washed with 2 X 5 ml of water and dried in a vacuum oven. 0.73 g of a solid was obtained. Yield: 0.73 g (88%) MR: corresponds to the free base of amlodipine DSC: Corresponds to Form I of the free base of amlodipine. Reference Example 2, based on McDaid and Deasy 1.5 g of amlodipine besylate were dissolved in 30 ml of methanol. A solution of 1 M NaOH (3.1 ml) was added. 40 ml of diethyl ether was added. No separation of layers was observed. 10 ml of water was added. The layers were separated and the organic layer was dried over Na2SO4. The mixture was evaporated to dryness and the solid obtained was dried in a vacuum oven. 0.85 g of a solid was obtained. Yield: 0.85 g (78%) NMR: corresponds to the free base of amlodipine DSC: corresponds to Form I of the free base of amlodipine. Reference Example 3 6 kg of amlodipine besylate in 12 1 of 2-propanol were suspended. They were shaken at 200 RPM for 15 minutes. 1M NaOH solution in water (10.6 1) was added. No exothermic effect was observed. It was stirred at 200 RPM for 1 hour. 20 1 of water were added in 10 minutes, seed crystals were added. 4 1 of water was added, a small exothermic effect was observed due to crystallization. The stirring speed was adjusted to 150 RPM, and stirred for 1 hour at 20 ° C. The reaction mixture was cooled to 5 ° C in 2 hours and stirred at 5 ° C for 30 minutes. The solid was separated by filtration and washed with 2 X 5 1 of water. The solid was dried in a vacuum oven at 40 ° C for 4 days. Yield: 4.05 g (93.5%) of slightly yellow crystals, average particle size approximately 230 microns. Purity: 99.7% NMR: corresponds to the free base of amlodipine The DSC and IR spectra showed Form I The XRPD is shown in Figure 1.

Example 1. Synthesis of amlodipine free base. 250 ml of 40% methylamine in water was stirred and 31. 5 g of phthalodipine at 40 ° C - 45 ° C for 16 hours. 460 ml of toluene were added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 150 ml of water. The layers were separated and the organic layer was evaporated to dryness. The solid obtained was dried at 40 ° C in a vacuum oven. 21.6 g of a solid were obtained. Yield: 21.6% (92%) HPLC: 98.8% PF area: 136 ° C - 139 ° C (uncorrected) IR: corresponds to Form I shown in Figure 2. DSC: corresponds to Form I that is shown in figure 3. Example 2. Synthesis of amlodipine free base 100 ml of 40% methylamine in water was stirred and 12. 6 g of phthalodipine at 40 ° C- 45 ° C for 16 hours. 150 ml of toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 50 ml of water. The mixture was reduced to approximately 20 ml and cooled, under stirring, in an ice bath. A solid started to precipitate, which was separated by filtration and washed with 5 ml of toluene. The solid product was dried in a vacuum oven. HPLC: 98.8% of NMR area: corresponds to amlodipine base DSC: corresponds to Form I of amlodipine base Example 3. Synthesis of free base of amlodipine 100 ml of 40% methylamine in water and 12.6 g of phthalodipine were stirred 40 ° C- 45 ° C for 16 hours. The mixture was separated by filtration and the solid obtained was washed with 2 X 10 ml of water. The solid was dried in a vacuum oven. Performance: 6 g (64%) HPLC: 98.8% of NMR area: corresponds to amlodipine base DSC: corresponds to Form I of amlodipine base Example 4a. Crystallization of the base amlodipine to form Form I 6.5 g of the crude amlodipine free base of Example 1 was dissolved in 60 ml of boiling ethanol. 120 ml of water was added and the mixture was allowed to cool to room temperature. During the cooling a solid began to precipitate. The mixture was cooled on an ice bath for 1 hour. The solid was separated by filtration and washed with 10 ml of water. The solid was dried in a vacuum oven at 40 ° C. 5.8 g of a solid were obtained. Yield: 5.8 g (89%) HPLC: 99.3% of the PF area: 140 ° C-141 ° C (uncorrected) IR: corresponds to Form I shown in figure 4. DSC: corresponds to Form I that is shown in Figure 5. Example 4b 2.0 g of free amlodipine base were dissolved in 5 ml of ethyl acetate by heating under reflux, and filtered over a Hyflo filter to obtain a clear solution. This hot solution was added dropwise to 100 ml of heptane under vigorous stirring. Amlodipine precipitated from the mixture and was isolated by filtration. The crystals (fine powder) were dried in vacuo at room temperature. Example 5a. Crystallization of amlodipine base to form Form II 6.5 g of amlodipine free base of Example 1 was dissolved in 25 ml of boiling toluene. This mixture was added slowly, under filtration, in 15 minutes, to a solution of 300 ml of n-hexane at a temperature of 0 ° C - 3 ° C. During the addition the temperature of the n-hexane solution was kept below 3 ° C. The solid was separated by filtration and dried in vacuo at room temperature. 6.0 g of a white solid were obtained.

Yield: 6.0 g (92%) HPLC: 99.3% of the IR area: corresponds to the Form II shown in figure 6. PF: 138 ° C - 140 ° C (uncorrected) DSC: 100.12 ° C at the beginning and 140.39 ° C at the beginning as shown in Figure 7. Example 5b 5.0 g of the free base of amlodipine in 10 ml of ethyl acetate was dissolved by heating under reflux. Immediately after a clear solution was obtained, the hot mixture was forced to cool to -78 ° C (ice-dry / acetone). The crystallization did not take place. However, outside the dry ice bath, the solution suddenly solidified. The crystals (as a powder) were isolated by filtration, and dried in vacuo at room temperature. IR: corresponds to Form II Example 5c 2.0 g of free base of amlodipine were dissolved in 6 ml of ethyl acetate by heating under reflux. The hot solution was filtered on a Hyflo filter, to obtain a clear solution, and added dropwise to 100 ml of heptane under vigorous stirring at -78 ° C. The temperature of the heptane layer was kept below -70 ° C. The precipitate was collected by filtration and dried under vacuum at room temperature overnight. IR: corresponds to Form II. Example 5d 2.5 g of free amlodipine base were dissolved in 7 ml of ethyl acetate by heating under reflux. The hot solution was filtered off on a Hyflo filter and added dropwise to an ice-cooled (0 ° C) layer of 100 ml of heptane under vigorous stirring. The temperature of the heptane layer was maintained between 0 -1 ° C. The precipitate was isolated by filtration and dried under vacuum at room temperature overnight. IR: corresponds to Form II Example 5e 2.0 g of amlodipine free base was dissolved in ml of toluene by heating to reflux. The hot solution was filtered over a Hyflo filter, and added dropwise to a pre-cooled layer (0 ° C) of 100 ml of heptane under vigorous stirring. The temperature of the heptane layer was maintained between 0-1 ° C. The precipitate was isolated by filtration and dried under vacuum at room temperature overnight. IR: corresponds to Form II Example 6a. Synthesis of Form II Free Amlodipine Base 100 ml of 40% methylamine in water and 12.6 g of phthalodipine were stirred at 40 ° C ~ 45 ° C for 16 hours. 150 ml of toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 50 ml of water. The mixture was reduced to about 75 ml and cooled on ice-bath to about -10 ° C. A solid formed which was filtered off and washed with 5 ml of toluene. The solid product was dried in a vacuum oven. Yield: g (92%) HPLC: (98.8% of the area) NMR: corresponds to the free base of amlodipine DSC: corresponds to Form II of amlodipine base Example 6b. Synthesis of Form II Free Amlodipine Base 100 ml of 40% methylamine in water and 12.6 g of phthalodipine FB.ADP.010710.01 were stirred at 40 ° C - 45 ° C for 16 hours. 150 ml of toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 50 ml of water. The organic layer was reduced to 75 ml and cooled to -20 ° C. 75 ml of n-heptane was added. A solid started to precipitate and separated by filtration. The solid was washed with 2 X 5 ml of n-heptane and dried in a vacuum oven. 7.9 g of a solid were obtained.

Yield: 7.9 g (85%) HPLC: (98.8% of area) NMR: corresponds to free base of amlodipine IR: corresponds to Form II DSC: corresponds to Form II Example 7. Conversion of Form II of amlodipine base to Form I 1 g of Form II of amlodipine base was heated at 115 ° C for 4 hours. The compound became slightly yellow. 0.9 g of a solid was recovered. IR: corresponds to the free base of amlodipine DSC: corresponds to Form I Example 8. Purification of amlodipine base via a salt 2.3 g of amlodipine were dissolved crude base in 50 ml of toluene. 150 ml of a 0.05 M HCl solution was added and the mixture was stirred vigorously. The layers wseparated and 10 ml of a 1 M NaOH solution was added to the aqueous layer. A solid was started and the mixture was stirred for 45 minutes at 3 ° C-5 ° C. The solid was separated by filtration and washed with 2 X 5 ml of water. The solid was dried in a vacuum oven. 1.65 g of a solid wobtained. Yield: 1.65 g (72%) NMR: corresponds to amlodipine base DSC: corresponds to Form I of amlodipine base Example 9. Comparison of adhesion Tablets wmade with the following composition in an Excenter EO Compressor (Korsch): Besylate tablets of amlodipine 47.5% of Crystalline Cellulose (Avicel PH 112; EMC) 47.5% calcium sulfate dihydrate (Compactrol, Penwest Pharmaceuticals Co.) 5.0% amlodipine besylate Free base tablets of amlodipine 48.2% Microcrystalline Cellulose (Avicel PH 112; EMC) 48.2% calcium sulfate dihydrate (Compactrol, Penwest Pharmaceuticals Co.) 3.67 ¾ amlodipine base (Ex. Ref. 3) Tablet properties Punch diameter: 20 mm Tablet weight: 400 mg Hardness: approximately 200 N After 50 tablets, the tablet material was extracted from the punches using methanol and an ultrasound bath. This procedure was repeated for the outputs of 100, 150, 200, 250 and 300 tablets. The extracts together with the calibration samples of amlodipine were measured spectrometrically. The amount of amlodipine in the samples was calculated from the calibration curve and the total amount of Amlodipine extracted from both punches the upper and lower graph against the amount of tablets made. An average value for adhesion was calculated from the slope of the regression line by forcing the y-intercept of the line to zero. Average residual (adhesion) of amlodipine base: 0.55 g of ADP.cirf2. tablet-1 Average residual (adhesion) of amlodipine besilate: 1.16 μg of ADP.cm-2. tablet-1 Example 10. Pharmaceutical tablet comprising free base of amlodipine a) Composition for tablets with calcium bisphosphate / microcrystalline cellulose Lot number ABCDEF (mg) (mg) (mg) (mg) (mg) (mg) Amlodipine base 2.5 10 2.5 10 (from Ref. 3 Ex.) Amlodipine base 2.5 10 ground (from Ex. Ref. 3 ) Phosphate of 31.5 126.0 31.5 126.0 31.5 126.5 Anhydrous calcium Cellulose 62.05 248.1 62.05 248.1 62.05 248.1 Microcrystalline Glycolate 2.0 8.0 2.0 8.0 2.0 8.0 Sodium starch Stearate 1.0 4.0 1.0 4.0 1.0 4.0 Total Magnesium 99.05 396.1 99.05 396.1 99.05 396.1 Lots A, B, E and F of amlodipine base were manufactured as follows: - Amlodipine base were sieved through a 500 μ a sieve. - The other excipients had been sieved through a 850 μp sieve.

All excipients except magnesium stearate had been mixed in a free fall mixer for 15 minutes at approximately 25 rpm. - Magnesium stearate was added and the powder combination mixed for another 5 minutes at approximately 25 rpm. - 2.5 mg and 10 mg tablets were compressed using an eccentric Korsch EKO compressor. Batches C and D of amlodipine were made as follows: - Base AMLODIPINE was ground. - The other excipients had been sieved through a sieve of 850 Jim. - All excipients except magnesium stearate had been mixed in a free fall mixer for 15 minutes at approximately 25 rpm. - Magnesium stearate was added and the powder combination mixed for another 5 minutes at approximately 25 rpm. - 2.5 mg and 10 mg tablets were compressed using an eccentric Korsch EKO compressor. No problems were found with the production of the previous tablets. b) Composition for tablets based on microcrystalline cellulose Batch number GH (mg) (mg) Amlodipine base (eg .2.5 10 of Ref. 3) Microcrystalline cellulose 75.55 302.1 Pre-dried potato starch 20.0 80.0 Magnesium stearate 0.5 2.0 Talc 0.5 2.0 Total 99.05 396.1 Manufacturing process: - Amlodipine base was sieved through a 500 um sieve. - The other excipients had been sieved through a 850 um sieve. All excipients except magnesium stearate and talc had been mixed in a free-flowing mixer for 15 minutes at approximately 25 rpm. - Magnesium stearate and talc were added and the powder combination was mixed for another 5 minutes at approximately 25 rpm. - 2.5 mg and 10 mg tablets were compressed using an eccentric Korsch EK0 compressor. c) The dissolution profiles were recorded using the paddle equipment at a rotation speed of 75 RPM and a dissolution medium of 500 ml of 0.01 M hydrochloric acid. The dissolution samples were analyzed by XJV spectrometry at 237 nm.

Example 11. Composition for amlodipine-free base capsules Procedure: - Amlodipine base was sieved through a sieve of 500 Jim. The other excipients had been sieved through a 850 um sieve. - All excipients except magnesium stearate were mixed in a free fall mixer for 15 minutes at approximately 25 rpm. - Magnesium stearate was added and the powder combination mixed for another 5 minutes at approximately 25 μm. - Gelatin capsules were filled with this combination of powders. The invention which has been described, will be obvious to those skilled in the art who can easily make additional changes and modifications in the current implementation of the concepts and embodiments described herein or can be learned by practicing the invention, without departing of the spirit and scope of the invention as defined by the following claims.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore the content of the following claims is claimed as property: 1. A pharmaceutical composition for tablets characterized in that it comprises an effective amount of free base of amlodipine and minus one pharmaceutically acceptable excipient; wherein the tablet exhibits low residue in the punch.
2. Composition in accordance with the claim 1, characterized in that the tablet leaves an average residue on the tabletting punch of 0.7 μg.cm_2 per tablet or less.
3. Composition according to claim 1 or 2, characterized in that the excipient is a calcium phosphate.
4. Composition according to any one of claims 1 to 3, characterized in that the excipient is microcrystalline cellulose.
5. Composition in accordance with the claim 3, further characterized in that it comprises microcrystalline cellulose.
6. Composition according to claim 5, characterized in that the calcium phosphate is anhydrous calcium biphosphate.
7. Composition of, according to any of the preceding claims, characterized in that the free base of amlodipine is Form II free base of crystalline amlodipine.
8. Composition according to any one of claims 1 to 6, characterized in that the free base of amlodipine is the free base of amorphous amlodipine.
Composition according to any one of claims 1 to 6, characterized in that amlodipine is a mixture of Form I and Form II free base of crystalline amlodipine.
10. Composition according to any of the preceding claims, characterized in that the tablet contains 1 to 100 mg of the free base of amlodipine.
11. Free base of amlodipine of form II.
12. Method of treating or preventing hypertension, angina, or congestive heart failure, characterized in that it comprises administering an effective amount of free base of amlodipine to a patient in need of it.
13. A process characterized in that it comprises: deprotecting an N-protected amlodipine with a deprotecting agent to form the free base of amlodipine; precipitate the free base of amlodipine from a solution; and isolating the free base of precipitated amlodipine as a solid state.
Process according to claim 13, characterized in that the solution is formed by the deprotection step.
15. Process according to claim 14, characterized in that the solution contains water.
16. Process according to any of claims 13 to 15, characterized in that the N-protected amlodipine is phtalodipine of formula (2a):
17. Process according to claim 16, characterized in that the deprotecting agent is aqueous methylamine.
Process according to the preceding claims 13 to 17, characterized in that the deprotection step takes place in an aqueous solution or suspension.
19. Process according to claim 18, characterized in that it additionally comprises extracting the free base of amlodipine in a solvent immiscible with water to form the solution.
20. Process according to claim 19, characterized in that the solvent immiscible in water is toluene.
21. Process in accordance with the claims 13 -. 13-19, characterized in that the precipitation is a crystallization step.
22. Process according to claim 21, characterized in that the crystallization comprises cooling the solution.
23. Process according to claim 22, characterized in that the crystallization further comprises evaporating a portion of the solvent from the solution.
24. Process in accordance with the claims 21 to 23, characterized in that the crystallization comprises adding a counter solvent to the solution.
25. Process according to claims 21 to 24, characterized in that the crystallization starts at a temperature above 5 ° C.
26. Process according to any of claims 21 to 24, characterized in that the crystallization starts at a temperature of 5 ° C or less and the solution is based on a non-aqueous solvent.
27. Process according to any of claims 13 to 26, characterized in that the free base of isolated amlodipine is the free base of amlodipine of crystalline form I.
Process according to any one of claims 13 to 26, characterized in that the free base of isolated amlodipine is the free base of amlodipine of crystalline form II.
29. Process according to claims 13 to 28, characterized in that it additionally comprises dissolving the isolated amlodipine-free base in a non-aqueous purification solvent and crystallizing the dissolved free base of the purification solvent to form the free base of purified crystalline amlodipine.
30. A process for purifying the free base of amlodipine, characterized in that it comprises: crystallizing the free base of amlodipine from a non-aqueous solvent.
31. The process according to claim 30, characterized in that the crystallization produces free base crystals of amlodipine having an average particle size of 150 to 350 microns.
32. A free base population of amlodipine in the form of particles having an average particle size of at least 100 microns.
33. The population according to claim 32, characterized in that the particles are crystals.