DE60125981T2 - AMLODIPIN IN THE FORM OF THE FREE BASE - Google Patents

Description

BACKGROUND OF THE INVENTION

1. Field of the invention

The The present invention relates to the free base of amlodipine, compositions, which comprise the free base of amlodipine and the use of the free base of amlodipine in therapy.

2. Description related technology

The EP 089167 and the corresponding one US 4,572,909 disclose a class of substituted dihydropyridine derivatives as useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now generally known as amlodipine, has the following formula:

While amlodipine as a free base and as a pharmaceutically acceptable acid addition salt Generally, the amlodipine examples all provide amlodipine maleate ago; for example Examples 9, 11, 12 and 22 of EP 089167. The maleate salt is considered to be the most preferred acid addition salt identified. Surprisingly the free base of amlodipine is not characterized. The examples seem to describe the formation of the free base, but only as a solution / slurry (example 11) or as a residue, the after evaporation of the solvent remains (Examples 12 and 22). Only the amlodipine maleate salt is called from a solution precipitated (Examples 12 and 22).

Subsequently were EP 244944 and the corresponding one U.S. 4,879,303 directly for the besylate (or benzenesulfonate) salt of amlodipine. It is stated that the besylate salt gives certain advantages over the known salts comprising amlodipine maleate. Various amlodipine salts were compared for water solubility, stability, non-hygroscopicity, and tablet formability. The free base of amlodipine was included in the processability tests that included the determination of the amount of amlodipine remaining on the tablet post-puncture tablets. It was stated that the amlodipine free base tablets on the stamper left an average of 2.02 μg amlodipine / cm ² per tablet. The amlodipine besylate tablets were reported to leave an average of 1.17 μg amlodipine / cm ² per tablet. Therefore, the composition of the free base suffers from excessive stickiness on the tablet stamper and was not suitable for the preparation of solid dosage forms for peroral administration. The amlodipine besylate salt is described in Examples 1 and 5 herein as being prepared from slurried amlodipine free base, although no procedure is described for preparing the free base.

D. McDaid and P. B. Deasy in Int. J. of Pharmaceutics 133, 71-83 (1996) suggest the use of the amlodipine free base in a transdermal pharmaceutical such as a patch. The free base of amlodipine in the solid state was in the above article The structure of which was confirmed by NMR and was determined by a Melting point of 144 ° C and a water solubility of 77.4 mg / l. The solid amlodipine base was through Neutralization of a solution of amlodipine besylate prepared with sodium hydroxide. In a first Procedure, the besylate was dissolved in methanol at 20 ° C, treated with aqueous sodium hydroxide and the base extracted from the mixture by diethyl ether, wherein the diethyl ether was then evaporated. It should be noted that this Process that has been described is not reproducible, since diethyl ether is miscible with the reaction mixture. In a second procedure became a watery solution of the besylate at 50 ° C with a sodium hydroxide solution treated and the base crystallized after cooling to 4 ° C.

It would be beneficial to have an oral dosage form of amlodipine based on Amlodi free base to have a pin. Such a dosage form should preferably be equivalent to acid addition salt forms of amlodipine, particularly the commercial amlodipine besylate salt, and should not suffer significant manufacturing or stability problems. Further, it would be beneficial to provide a direct process for forming the free base of amlodipine, which may provide isolation by, inter alia, filtration.

SUMMARY THE INVENTION

The present invention is based on the study of the free base of amlodipine and the discovery of various physical properties thereof. Due to the realization of these properties, the present invention provides a useful pharmaceutical dosage form of the amlodipine free base, in particular a tablet, a newly crystalline form of the amlodipine free base, a population of amlodipine free base particles used in the preparation of a tablet are useful, and a method for more economical formation of the free base of amlodipine ready. Accordingly, a first aspect of the present invention relates to a pharmaceutical tablet composition comprising an effective amount of the amlodipine free base and at least one pharmaceutically acceptable diluent; wherein the free base of amlodipine is either (i) the crystalline form II; (ii) amorphous or (iii) a mixture of the crystalline Form I and Form II and the formed tablet leaves an average residue on the tablet stamp of 0.7 μg cm ^-2 per tablet or less.

One Another aspect of the present invention relates to the crystalline Form II of the free base of amlodipine. This new crystalline form Amlodipine is also for use as a pharmaceutically active Medium suitable.

One Another aspect of the present invention relates to a population of particulate free base of amlodipine with an average particle size of at least 100 μm. Preferably, the particles are crystals and the average Particle size 150 to 350 μm. Such a population of particles is in the formation of a Tablet composition usable.

One Another aspect of the invention relates to the use of the free Base of amlodipine in the manufacture of a drug for treatment or prevention of hypertension, angina or decompensated heart failure, wherein the method comprises administering an effective amount of the free Base of amlodipine to a patient in need of this. Preferably, the free base of amlodipine in the above Administered tablet form.

One Yet another aspect of the present invention relates to a method that deprotecting an N-protected Amlodipine with a deprotecting agent with the formation of the free base of amlodipine, the precipitation of the free base of amlodipine from a solution and isolating the precipitated free base of amlodipine in solid form. The solution, out which precipitates the amlodipine free base can be removed by the deprotection step solution obtained or a different solution, i.e. in an extraction solvent, be.

One Another aspect of the present invention relates to a method for purifying the free base of amlodipine, which is crystallizing free base of amlodipine from a nonaqueous solvent. advantageously, Crystallization gives crystals of the free base of amlodipine with an average particle size of 150 to 350 microns.

SHORT DESCRIPTION THE DRAWINGS

1 Fig. 10 shows a powder X-ray diffraction pattern for the amlodipine free base (Form I) of Reference Example 3.

2 Figure 4 shows an IR spectrum of the crystalline free base of amlodipine (Form I) of Example 1.

3 shows a DSC curve of the crystalline free base of amlodipine (Form I) of Example 1.

4 Figure 4 shows an IR spectrum of the crystalline free base of amlodipine (Form I) of Example 4a.

5 shows a DSC curve of the crystalline free base of amlodipine (Form I) of Example 4a.

6 Figure 4 shows an IR spectrum of the crystalline free base of amlodipine (Form II) of Example 5a.

7 Figure 4 shows a crystalline free base DSC curve of amlodipine (Form II) of Example 5a.

8th Figure 3 shows a powder X-ray diffraction pattern of the crystalline free base of amlodipine (Form II) of Example 5b.

DETAILED DESCRIPTION OF THE INVENTION

A tablet of the amlodipine free base according to the present invention is a low stain residue tablet. The term "low stamp residue" as used herein means that the average amount of amlodipine remaining on a tablet stamper does not exceed 0.7 μg.cm ^-2 per tablet, based on a 20 mm round flat punch with a compressive force of 15 kN, preferably 0, 6 μg · cm ^-2 per tablet. The amount of amlodipine residue can be determined by the method according to the treatment in EP 244944 be determined. Generally, the process involves washing the stamp after passing 50, 100, 150, 200, 250 and 300 tablets using methanol and an ultrasonic bath. The amount of amlodipine in the samples is determined by UV and the total amount of amlodipine extracted from both the upper and lower punches is plotted against the amount of tablet produced. An average value for the amlodipine residue (stickiness) is calculated from the slope of the regression curve by moving the Y-section of the curve through the zero point.

The Tablet comprises an effective amount of the amlodipine free base, from (i) the crystalline form II, (ii) amorphous material or (iii) a mixture of the crystalline form I and form II is selected, and at least one pharmaceutically acceptable diluent. One "extender" used herein means any pharmaceutically acceptable inactive component of the composition. As relevant extenders include diluents, binders, Lubricants, disintegrants, colorants, antioxidants / preservatives, pH adjusting agents and the like. The extenders are based on desired physical aspects of the finished form: for example, education a tablet with the desired hardness and friability, which is easily distributed and easy to swallow and the like., Selected. The desired release rate the active substance from the composition after ingestion also plays a role in the choice of extenders. For example can Preparations, if desired, be designed so that they release a slow release of the free Base of amlodipine revealed.

• – ein Verdünnungsmittel, wie Calciumhydrogenphosphat, Lactose, Mannit und dgl.
• – ein Bindemittel, wie mikrokristalline Cellulose oder eine modifizierte Cellulose, Povidone und dgl.
• – ein Desintegrationsmittel, wie Natriumstärkeglykollat, Crosspovidone
• – ein Gleitmittel, wie Magnesiumstearat, Natriumstearylfumarat, Talkum
• – ein Farbmittel, Geschmacksmaskierungsmittel und dgl.

Suitable extenders for use in this invention include:

• A diluent such as calcium hydrogen phosphate, lactose, mannitol and the like.
• A binder such as microcrystalline cellulose or a modified cellulose, povidone and the like.
• A disintegrating agent such as sodium starch glycollate, crosspovidone
• A lubricant such as magnesium stearate, sodium stearyl fumarate, talc
• A colorant, taste masking agent and the like.

The Tablets of the invention preferably do not require an antiblocking agent, like talc. The composition of the tablet preferably comprises a calcium phosphate extender and / or microcrystalline cellulose and even better, both calcium phosphate and microcrystalline ones Cellulose. An example for a calcium phosphate extender is anhydrous calcium hydrogen phosphate. Further, the tablet may contain other conventional diluents, such as binders, Lubricants, disintegrants, colorants, preservatives and the like. included.

The free base of amlodipine can be either (i) the crystalline form II, (ii) amorphous or (iii) a mixture of the crystalline form II and form I. Form I is characterized by a powder X-ray diffraction pattern, which is shown in FIG 1 is indicated, an IR spectrum that in 2 or 4 and a single melting endotherm on the DSC curve with insertion at about 140 ° C 3 and 5 is indicated. This shape corresponds to the material described by McDaid and Deasy. The Form II is a new form and characterized by a different powder X-ray diffraction pattern in 8th is indicated, an IR spectrum that in 6 and a DSC curve determined by a transition endotherm or endotherm at a temperature of about 100 ° C and a melting endotherm at about 140 ° C, which are described in U.S. Pat 7 are indicated. Although it is possible to convert Form II to Form I by using sufficiently high temperatures, generally above 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 at 60 ° C. Accordingly, Form II is therefore useful in the preparation of finished pharmaceutical forms. As indicated, the free base of amlodipine in the tablet of the present invention may be a single species, ie, crystalline form II or amorphous, or it may be a mixture of crystalline forms I and II.

to Decreasing the stickiness of the tablets is generally desired, the Size of the free Base of amlodipine and / or the extenders used to control. In particular, it is preferred if the free base of amlodipine into the tablet composition in the form of particles having a average particle size of at least 100 μm, preferably 150 to 350 μm, even better 200 to 300 μm, is incorporated. The particles are generally free crystals Base of amlodipine, although non-crystalline forms also incorporated can be. The moisture in the tablet is preferably limited to the Reduce stickiness. The preferred extenders are calcium phosphate and microcrystalline cellulose as described above.

The Amlodipine free base amount is not specifically limited and it includes any amount that gives a pharmaceutical effect. In particular, the free base of amlodipine may be used for treatment or prevention from hypertension, decompensated heart failure or angina Administering an effective amount to one that requires it Patients are used. The special form of angina is not specially limited and it specifically includes chronic stable angina and Vasospastic angina (Prinzmetal's angina). The "patients" to be treated include Human and non-human patients, especially human and non-human Mammal. General amounts the amount of free base of amlodipine in a unit dose 1 to 100 mg, more typically 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 preferably between 2 and 10%.

worin N-Prot eine Aminogruppe, die durch eine abspaltbare Schutzgruppe, wie eine Benzylgruppe oder Tritylgruppe, geschützt ist oder mit einer in eine Amingruppe umwandelbaren Gruppe, wie einer Phthalimidogruppe oder Azidogruppe, maskiert ist, bedeutet. In einer bevorzugten Ausführungsform ist das geschützte Amlodipin eine Phthalimido-geschützte Amlodipinverbindung der Formel (2a):

The free base of amlodipine used in the tablet of the present invention can be prepared by any conventional means. Preferably, the free base is formed and isolated by a method comprising deprotecting an N-protected amlodipine with a deprotecting agent to form the amlodipine free base, precipitating the amlodipine free base from a solution, and isolating the precipitated amlodipine free base in solid form. An N-protected amlodipine is an amlodipine compound wherein the terminal amino group is protected as indicated in formula (2):

wherein N-Prot means an amino group protected by a releasable protective group such as a benzyl group or trityl group, or masked with a group convertible to an amine group such as a phthalimido group or azido group. In a preferred embodiment, the protected amlodipine is a phthalimido-protected amlodipine compound of the formula (2a):

This protected Amlodipine is hereinafter often referred to as phthalodipine.

According to the invention, the free base of amlodipine in the solid state can be prepared by appropriately working up the reaction mixture obtained after the last step of synthesis leading to amlodipine, ie the step comprising deprotection of the amlodipine precursor of the above formula (2). Suitable deprotecting agents are known in the art and the selection thereof depends on the one used Protective group. The free base of amlodipine is obtained without the need for formation and, above all, the isolation of an amlodipine salt. The process is characterized in that no acidic agent or medium is used for deprotection nor for work-up purposes, ie, the deprotected amlodipine free base is the free base which precipitates without the intermediate formation of an amlodipine salt.

The Process of the present invention requires "precipitation" of amlodipine free base from one Solution. A precipitation is a well-known phenomenon whereby a solid phase is separated from a solution. An advantage a precipitation is that the solid phase comprising the desired product differs from the liquid Phase, which is the solvent and soluble Co-products, i. By-products or impurities, comprises, can be separated. A precipitation is therefore also a tool to at least some impurities get rid of the product. This is not possible if a solid product from a solution by simply evaporating off the solvent is obtained. Therefore includes for the purpose of the present invention is a precipitation not just the evaporation of the entire solvent in a solution leaving behind a residue. The precipitation is preferably a crystallization, although not on it is limited. A precipitation, which includes a reduction in the temperature of the solution generally results to a crystallization while a precipitate, the one change of the pH, to a classical precipitation of the solid in either crystalline or non-crystalline form can lead. The solution can directly through the deprotection stage be formed or it may be a different solution, for example one formed by an extraction process. The solution can aqueous, non-aqueous or a solvent mixture be. General leads an aqueous one solvent for the formation of small particle sizes. The Purification step described hereinafter may be used to get particles of the amlodipine free base of a larger size, such as desired to obtain.

The Isolation of the precipitated solid form of the amlodipine free base may be any suitable or known separation technique a solid phase of a liquid Phase, i. a solvent or a solution, be. Preferably, the isolation step uses a filtration.

The invention will be described in relation to its preferred embodiment wherein phthalodipine of the formula (2a) is used as the N-protected amlodipine compound. Corresponding EP 89167 phthalodipine is deprotected either by ethanolic methylamine, ethanolic hydrazine hydrate or by KOH in a water / tetrahydrofuran mixture. These techniques are suitable for the process of our invention, but they are quite uneconomical. In a more advantageous manner, the deprotection is carried out by treatment of phthalodipine with an aqueous methylamine solution. The advantage of an aqueous methylamine solution is that the amlodipine free base readily separates from the reaction mixture and can easily be isolated in the solid state by filtration. The co-product of the deprotection reaction (N-methylphthalimide) remains in the aqueous solution.

The Reaction with aqueous Methylamine can be used at a temperature from ambient to about 60 ° C, preferably at 30-50 ° C carried out become. The course of the reaction can be determined by any suitable analytical technique, which allows separation of the starting material and the product, for example by HPLC become. The product can be filtered by filtration at 5-25 ° C, preferably be separated at ambient temperature.

In Alternatively, the reaction mixture containing the free Base of amlodipine comprises, by extraction of amlodipine from the alkaline aqueous solution by a water-immiscible organic solvent, For example, toluene, worked up. The extraction temperature is essentially ambient temperature. Concentration of the extraction solution allows the precipitation crude free base of amlodipine in the solid state. A Kontralösemittel (For example, hexane) may also be added to the extraction solution, in particular to the concentrated solution, given be to the precipitation to allow the free base of amlodipine in the solid state.

Further, crude solid free base of amlodipine can be purified by various techniques. It should be noted that the meaning of "crude solid" amlodipine is not limited only to the solid amlodipine base prepared by the above process of our invention, but includes any solid amlodipine base which is to be further purified. Purification is used herein in a broad sense to include an improvement in crystal size, ie, the removal of small crystals in favor of larger crystals, as well as a reduction in the concentration of impurities in the amlodipine free base. In particular, precipitation from aqueous solutions generally gives free base of amlodipine as fine particles. Purification via a crystallization purification step can be used to obtain crystals of the crystals free base of amlodipine with a larger, more favorable particle size can be used.

• – durch spontanes oder zwangsweises Kühlen der Lösung der freien Base von Amlodipin
• – durch Zugabe eines zumindest teilweise mischbaren Kontralösemittels zu einer Lösung der freien Base von Amlodipin (unter Rühren oder unter Diffusion), optional in Kombination mit spontanem oder zwangsweisem Kühlen
• – durch Abdampfen eines Teils des Lösemittels, optional in Kombination mit einer der vorhergehenden Techniken.

In a first purification process, the free base of amlodipine is crystallized from a solution based on a suitable nonaqueous solvent, hereinafter sometimes referred to as a "cleaning solvent". Preferably, the dissolution of amlodipine in the solvent is conducted at elevated temperature, which may also include the boiling temperature of the cleaning solvent. If desired, the resulting solution may be further purified by conventional adsorption techniques, for example by treatment with activated charcoal or silica gel, prior to crystallization. The crystallization from a solution can be carried out in different ways:

• By spontaneous or forced cooling of the free base solution of amlodipine
• - by adding an at least partially miscible Kontralösemittels to a solution of the free base of amlodipine (with stirring or under diffusion), optionally in combination with spontaneous or forced cooling
• By evaporation of a portion of the solvent, optionally in combination with one of the preceding techniques.

suitable solvent include aliphatic C1-C4 alcohols, such as methanol or ethanol, chlorinated C 1 -C 4 hydrocarbons, such as chloroform, alkyl esters 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 Kontralösemittel can either stronger polar as the solvent an example being water, or less polar than that solvent an example being hexane or heptane.

at Another purification procedure becomes crude free base of amlodipine in a suitable, water-immiscible or hardly miscible Cleaning solvents, for example, toluene, dissolved, the toluene solution with an aqueous Acid extracted, being an aqueous solution an amlodipine salt, which is then replaced by a base, For example, an alkali or amine is neutralized. The educated Amlodipine base can be made from the watery solution precipitated and separated or into an organic solvent, which is immiscible with water or hardly miscible, back-extracted then cooled, concentrated or with a Kontralösemittel is mixed, whereby purified free base of amlodipine precipitates out of the solution. The Nature of the acid should preferably be chosen be that the amlodipine salt formed is soluble in water. A suitable acid is hydrochloric acid.

The Free base of amlodipine in solid form can also be obtained by freeze-drying a solution same, for example, a solution in ethanol-water (2: 1), getting produced.

By any of the above manufacturing or purification processes except working under conditions that are discussed below the amlodipine free base was obtained in the crystalline form I.

Under certain conditions may be a new polymorph form of free base of amlodipine in solid state (Form II) from solutions of the free base of Amlodipine be prepared. Generally, the conditions require that crystallization at low temperatures and typically begins with rapid cooling, to avoid the formation of Form I nuclei. For example Form II is formed when a solution of the free base of amlodipine in a non-aqueous Solvents in toluene, for example, with a control solvent, for example hexane, Cyclohexane or heptane, treated at temperatures below 5 ° C. becomes. The "solution of free base of amlodipine in a nonaqueous solvent "includes the crude solution, for example, toluene solution, the after the above deprotection step was obtained. The addition of a control solvent includes adding a control solvent in the chilled or cooled expectant solution of free base of amlodipine or the application of the solution of free base of amlodipine on a cooled Kontralösemittel. General allows the use of a counter-solvent the use of a higher Crystallization temperature in the formation of the form II.

In In an alternative method, Form II can be precipitated by precipitation forced cooling a solution the free base of amlodipine in a suitable crystallization solvent, for example, ethyl acetate, the precipitate being at a temperature of less than 5 ° C, even better below -5 ° C and even cheaper at -10 ° C or below, which is -20 ° C and including, begins.

It should be noted that the free base of amlodipine, in particular the crystalline form II of the free base of amlodipine and the purified free base of amlodipine described above, also as Zwischenpro can be used in the preparation of amlodipic acid addition salts. Advantageously, amlodipine base purified by methods of the invention is reacted with a pharmaceutically acceptable acid to form an amlodipine salt which exhibits a desired degree of purity, for example pharmaceutical purity, without the need for further purification.

Amlodipinsalze can by, for example, treating the solution or suspension of the amlodipine base in a suitable solvent with an equivalent Amount of an acid and isolating the formed salt from the reaction mixture become. Include amlodipin salts producible by this process preferably, but not limited to, salts with pharmaceutical acceptable acids, Examples include amlodipine maleate, fumarate, hydrogen maleate, besylate, -sylate monohydrate, besylate dihydrate, hydrochloride, mesylate, mesylate monohydrate, hydrobromide, citrate and tartrate.

suitable Process for the preparation of a tablet of the amlodipine free base can any conventional Methods include. The compositions of this invention may be characterized by conventional Mixing processes, such as mechanical mixing, filling and compression, by wet granulation, Dry granulation or direct compression can be formulated. The the latter method is most advantageous and a preferred one for the Tablet composition of the invention used on an industrial scale become.

While the present invention primarily directed to tablets, a capsule dosage form may also be used be prepared from the free base of amlodipine. The capsule compositions can essentially the same diluents as for tablet compositions include. An advantageous inert carrier is microcrystalline cellulose without calcium phosphate.

The amlodipine free base may also be used in medical applications in combination with other antihypertensive agents and / or antianginal agents, for example with ACE inhibitors such as benazepril. The combination may be in the form of a single combination preparation, for example a capsule containing the free base of amlodipine and benazepril hydrochloride or by separate administration of drugs containing the above agents. The amlodipine free base can also be used in combination with various cholesterol-lowering drugs such as lovastatin, simvastatin or atorvastastin. The free base of amlodipine may be used in the treatment of the following disorders:
hypertension
chronic stable angina pectoris
Vasospastic angina (Prinzmetal's angina)
decompensated heart failure
be used.

These disorders will be referred to as "the Disturbances " The present invention further provides a method of treatment and / or prevention from one or more of the disorders by administering an effective and / or prophylactic amount the free base of amlodipine in a composition of the invention to a sufferer who needs it. An effective amount is relevant known. For example, is in humans an effective amount typically between 1 and 100 mg of the free base of amlodipine. One dose unit, described earlier is usually 1 to 3 times a day, preferably once taken during the day. In practice, the doctor determines the actual Dosage and dosage regimen for the individual patient most suitable.

The The present invention also provides the use of the composition of the invention in the manufacture of a medicament for treatment and / or prevention ready for one or more of the faults.

• Ausbeute: 4,05 kg (93,5 %) hellgelber Kristalle, durchschnittliche Teilchengröße etwa 230 μm.
• Reinheit 99,7
• NMR: entspricht der freien Base von Amlodipin
• DSC und IR zeigten die Form I
• XRPD ist in 1 angegeben.

Beispiel 1 Synthese der freien Base von Amlodipin 250 ml von 40 % Methylamin in Wasser und 31,5 g Phthalodipin wurden bei 40 °C-45 °C 16 h gerührt. 460 ml Toluol wurden zugegeben und das Gemisch wurde 30 min gerührt. Die Schichten wurden getrennt und die organische Schicht wurde mit 150 ml Wasser gewaschen. Die Schichten wurden getrennt und die organische Schicht wurde zur Trockne eingedampft. Der erhaltene Feststoff wurde bei 40 °C in einem Vakuumofen getrocknet. 21,6 g Feststoff wurden erhalten.

• Ausbeute: 21,6 g (92 %)
• HPLC: 98,8 Flächenprozent
• Fp: 136 °C-139 °C (unkorrigiert)
• IR: entspricht der Form I wie in 2 angegeben.
• DSC: entspricht der Form I wie in 3 angegeben.

Beispiel 2 Synthese der freien Base von Amlodipin 100 ml von 40 % Methylamin in Wasser und 12,6 g Phthalodipin wurden bei 40 °C-45 °C 16 h gerührt. 50 ml Toluol wurden zugegeben und das Gemisch wurde 30 min gerührt. Die Schichten wurden getrennt und die organische Schicht wurde mit 150 ml Wasser gewaschen. Das Gemisch wurde auf etwa 20 ml verringert und unter Rühren auf einem Eisbad gekühlt. Ein Feststoff begann auszufallen, der abfiltriert wurde und mit 5 ml Toluol gewaschen wurde. Das feste Produkt wurde in einem Vakuumofen getrocknet.

• HPLC: 98,8 Flächenprozent
• NMR: entspricht der Amlodipinbase
• DSC: entspricht der Form I der Amlodipinbase

Beispiel 3 Synthese der freien Base von Amlodipin 100 ml von 40 % Methylamin in Wasser und 12,6 g Phthalodipin wurden bei 40 °C-45 °C 16 h gerührt. Das Gemisch wurde filtriert und der erhaltene Feststoff wurde mit 2 × 10 ml Wasser gewaschen. Der Feststoff wurde in einem Vakuumofen getrocknet.

• Ausbeute: 6 g (64 %)
• HPLC: 98,8 Flächenprozent
• NMR: entspricht der Amlodipinbase
• DSC: entspricht der Form I der Amlodipinbase

Beispiel 4a Kristallisation der Amlodipinbase zur Bildung von Form I 6,5 g der rohen freien Base von Amlodipin von Beispiel 1 wurden in 60 ml siedendem Ethanol gelöst. 120 ml Wasser wurden zugegeben und das Gemisch wurde auf Raumtemperatur abkühlen gelassen. Während des Abkühlens beginnt ein Feststoff auszufallen. Das Gemisch wurde auf einem Eisbad 1 h gekühlt. Der Feststoff wurde abfiltriert und mit 10 ml Wasser gewaschen. Der Feststoff wurde in einem Vakuumofen bei 40 °C getrocknet. 5,8 g eines Feststoffs wurden erhalten.

• Ausbeute: 5,8 g (89 % )
• HPLC: 99,3 Flächenprozent
• Fp: 140 °C-141 °C (unkorrigiert)
• IR: entspricht der Form I wie in 4 angegeben.
• DSC: entspricht der Form I wie in 5 angegeben.

Beispiel 4b 2,0 g der freien Base von Amlodipin wurden in 5 ml Ethylacetat durch Erhitzen unter Refluxieren gelöst und über Hyflo filtriert, wobei eine klare Lösung erhalten wurde. Diese warme Lösung wurde tropfenweise zu 100 ml Heptan unter kräftigem Rühren gegeben. Amlodipin fiel aus dem Gemisch aus und wurde durch Filtration isoilert. Die Kristalle (feines Pulver) wurden unter Vakuum bei Raumtemperatur getrocknet. Beispiel 5a Kristallisation der Amlodipinbase unter Bildung von Form II 65 g der freien Base von Amlodipin von Beispiel 1 wurden in 25 ml siedendem Toluol gelöst. Dieses Gemisch wurde langsam in 15 min zu 300 ml einer n-Hexanlösung von 0-3 °C unter Rühren gegeben. Während der Zugabe wurde die Temperatur der n-Hexanlösung unter 3 °C gehalten. Der Feststoff wurde abfiltriert und unter Vakuum bei Umgebungstemperatur getrocknet. 6,0 g eines weißen Feststoffs wurden erhalten.

• Ausbeute: 6,0 g (92 %)
• HPLC: 99,3 Flächenprozent
• IR: entspricht der Form II wie in 6 angegeben.
• FP: 138-140 °C (unkorrigiert)
• DSC: Einsetzen bei 100,12 °C und Einsetzen bei 140,39 °C wie in 7 angegeben.

Beispiel 5b 5,0 g der freien Base von Amlodipin wurden in 10 ml Ethylacetat durch Erhitzen unter Refluxieren gelöst. Unmittelbar nach dem Erhalte einer klaren Lösung wurde das Gemisch zwangsweise auf -78 °C (Trockeneis/Aceton) abgekühlt. Es erfolgte keine Kristallisation. Jedoch verfestigte sich die Lösung plötzlich außerhalb des Trockeneisbads. Die Kristalle (pulverähnlich) wurden durch Filtration isoliert und unter Vakuum bei Raumtemperatur getrocknet.

• IR: entspricht der Form II

Beispiel 5c 2,0 g der freien Base von Amlodipin wurden in 6 ml Ethylacetat durch Erhitzen unter Refluxieren gelöst. Die heiße Lösung wurde über Hyflo filtriert, wobei eine klare Lösung erhalten wurde, und tropfenweise zu 100 ml Heptan unter kräftigem Rühren bei -78 °C gegeben. Die Temperatur der Heptanschicht wurde unter -70 °C gehalten. Der feste Niederschlag wurde durch Filtration gewonnen und unter Vakuum bei Raumtemperatur über Nacht getrocknet.

• IR: entspricht der Form II.

Beispiel 5d 2,5 g der freien Base von Amlodipin wurden in 7 ml Ethylacetat durch Erhitzen unter Refluxieren gelöst. Die heiße Lösung wurde über Hyflo filtriert und tropfenweise zu einer eiskalten (0 °C) Schicht von 100 ml Heptan unter kräftigem Rühren gegeben. Die Temperatur der Heptanschicht wurde zwischen 0 und 1 °C gehalten. Der Niederschlag wurde durch Filtration isoliert und unter Vakuum bei Raumtemperatur über Nacht getrocknet.

• IR: entspricht der Form II

Beispiel 5e 2,0 g der freien Base von Amlodipin wurden in 10 ml Toluol durch Erhitzen unter Refluxieren gelöst. Die heiße Lösung wurde über Hyflo filtriert und tropfenweise zu einer vorgekühlten (0 °C) Schicht von 100 ml Heptan unter kräftigem Rühren gegeben. Die Temperatur der Heptanschicht wurde zwischen 0 und 1 °C gehalten. Der Niederschlag wurde durch Filtration isoliert und unter Vakuum bei Raumtemperatur über Nacht getrocknet.

• IR: entspricht der Form II

Beispiel 6a Synthese der Form II der freien Base von Amlodipin 100 ml von 40 % Methylamin in Wasser und 12,6 g Phthalodipin wurden 16 h bei 40-45 °C gerührt. 150 ml Toluol wurden zugegeben und das Gemisch wurde 30 min gerührt. Die Schichten wurden getrennt und die organische Schicht wurde mit 50 ml Wasser gewaschen. Das Gemisch wurde auf etwa 75 ml verringert und auf einem Eis/Salzbad auf etwa -10 °C gekühlt. Ein Feststoff wurde gebildet, der abfiltriert und mit 5 ml Toluol gewaschen wurde. Das feste Produkt wurde in einem Vakuumofen getrocknet.

• Ausbeute: g (92 %)
• HPLC: 98,8 Flächenprozent
• NMR: entspricht der freien Base von Amlodipin
• DSC: entspricht der Form II der Amlodipinbase

Beispiel 6b Synthese der Form II der freien Base von Amlodipin 100 ml von 40 % Methylamin in Wasser und 12,6 g Phthalodipin FB.ADP.010710.01 wurden bei 40 °C-45 °C 16 h gerührt. 150 ml Toluol wurde zugegeben und das Gemisch wurde 30 min gerührt. Die Schichten wurden getrennt und die organische Schicht wurde mit 50 ml Wasser gewaschen. Die organische Schicht wurde af 75 ml verringert und auf -20 °C gekühlt. 75 ml n-Heptan wurden zugegeben. Ein Feststoff begann auszufallen, der abfiltriert wurde. Der Feststoff wurde mit 2 × 5 ml n-Heptan gewaschen und in einem Vakuumofen getrocknet. 7,9 g eines Feststoffs wurden erhalten.

• Ausbeute: 7,9 g (85 %)
• HPLC: 98,8 Flächenprozent
• NMR: entspricht der freien Base von Amlodipin
• IR: entspricht der Form II
• DSC: entspricht der Form II

Beispiel 7 Umwandlung der Form II der Amlodipinbase in die Form I 1 g der Form II der Amlodipinbase wurde 4 h bei 115 °C erhitzt. Die Verbindung wurde leicht gelb. 0,9 g eines Feststoffs wurden gewonnen.

• IR: entspricht der freien Base von Amlodipin
• DSC: entspricht der Form I

Beispiel 8 Reinigung der Amlodipinbase über ein Salz 2,3 g der rohen Amlodipinbase wurden in 50 ml Toluol gelöst. 150 ml einer 0,05 M HCl-Lösung wurden zugegeben und das Gemisch wurde kräftig geschüttelt. Die Schichten wurden getrennt und zu der wässrigen Schicht wurden 10 ml einer 1 M NaOH-Lösung gegeben. Die Bildung eines Feststoffs begann und das Gemisch wurde 45 min bei 3-5 °C gerührt. Der Feststoff wurde abfiltriert und mit 2 × 5 ml Wasser gewaschen. Der Feststoff wurde in einem Vakuumofen getrocknet. 1,65 g eines Feststoffs wurden erhalten.

• Ausbeute: 1,65 g (72 %)
• NMR: entspricht der Amlodipinbase
• DSC: entspricht der Form I der Amlodipinbase

The following examples illustrate the invention, but should not be construed as limiting the invention thereto. Reference Example 1 is based on McDaid and Deasy. 1.15 g Amlodipine besylate was in 250 ml Dissolved water at 50 ° C-55 ° C. 2.2 ml of a 1M NaOH solution was added. The mixture was brought to 3 ° C-5 ° C and stirred for 1 h at this temperature. The solid was filtered off and washed with 2 x 5 ml Washed water and dried in a vacuum oven. 0.73 g of a solid were obtained. Yield: 0.73 g (88%) NMR: corresponds to the free base of amlodipine DSC: corresponds to the form I of the free base of amlodipine Reference Example 2 based on McDaid and Deasy 1.5 g Amlodipine besylate was in 30 ml Dissolved methanol. 3.1 ml of a 1M NaOH solution was added. 40 ml Diethyl ether was added. No separation of layers was observed. 10 ml Water was added. Layers separated and the organic layer was dried over Na ₂ SO ₉ . The mixture was evaporated to dryness and the resulting solid was dried in a vacuum oven. 0.85 g of a solid were obtained. Yield: 0.85 g (78%) NMR: corresponds to the free base of amlodipine DSC: corresponds to the form I of the free base of amlodipine Reference Example 3 6 kg Amlodipine besylate was in 12 l Suspended 2-propanol. It was stirred for 15 min at 200 rpm. 10.6 l 1M NaOH in water was added. No exothermic effect was observed. It was stirred for 1 h at 200 rpm. 20 l Water was added in 10 minutes, seed crystals were added. 4 l Water was added, a small exothermic effect was observed due to crystallization. The stirring rate was set to 150 rpm and it was stirred at 20 ° C for 1 h. The reaction mixture was cooled to 5 ° C in 2 h and stirred at 5 ° C for 30 min. The solid was filtered off and washed with 2 × 5 l Washed water. The solid was dried in a vacuum oven at 40 ° C for 4 days.

• Yield: 4.05 kg (93.5%) of light yellow crystals, average particle size about 230 μm.
• Purity 99.7
• NMR: corresponds to the free base of amlodipine
• DSC and IR showed the form I
• XRPD is in 1 specified.

Example 1 Synthesis of Amlodipine Free Base 250 ml of 40% methylamine in water and 31.5 g Phthalodipine were stirred at 40 ° C-45 ° C for 16 h. 460 ml Toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 150 ml Washed water. The layers were separated and the organic layer was evaporated to dryness. The resulting solid was dried at 40 ° C in a vacuum oven. 21.6 g Solid were obtained.

• Yield: 21.6 g (92%)
• HPLC: 98.8 area percent
• Mp: 136 ° C-139 ° C (uncorrected)
• IR: corresponds to the form I as in 2 specified.
• DSC: corresponds to the form I as in 3 specified.

Example 2 Synthesis of Amlodipine Free Base 100 ml of 40% methylamine in water and 12.6 g Phthalodipine were stirred at 40 ° C-45 ° C for 16 h. 50 ml Toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 150 ml Washed water. The mixture was reduced to about 20 ml and cooled with stirring on an ice-bath. A solid began to precipitate, which was filtered off and with 5 ml Toluene was washed. The solid product was dried in a vacuum oven.

• HPLC: 98.8 area percent
• NMR: corresponds to the amlodipine base
• DSC: corresponds to form I of amlodipine base

Example 3 Synthesis of Amlodipine Free Base 100 ml of 40% methylamine in water and 12.6 g Phthalodipine were stirred at 40 ° C-45 ° C for 16 h. The mixture was filtered and the resulting solid was washed with 2 x 10 ml Washed water. The solid was dried in a vacuum oven.

• Yield: 6 g (64%)
• HPLC: 98.8 area percent
• NMR: corresponds to the amlodipine base
• DSC: corresponds to form I of amlodipine base

Example 4a Crystallization of amlodipine base to form Form I 6.5 g of the crude amlodipine free base of Example 1 were in 60 ml dissolved boiling ethanol. 120 ml Water was added and the mixture was allowed to cool to room temperature. During cooling, a solid begins to precipitate. The mixture was cooled on an ice-bath for 1 h. The solid was filtered off and washed with 10 ml Washed 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 area percent
• Mp: 140 ° C-141 ° C (uncorrected)
• IR: corresponds to the form I as in 4 specified.
• DSC: corresponds to the form I as in 5 specified.

Example 4b 2.0 g The free base of amlodipine was in 5 ml Dissolved ethyl acetate by heating with refluxing and filtered through Hyflo to give a clear solution was obtained. This warm solution became dropwise 100 ml Heptane with vigorous stirring. Amlodipine precipitated from the mixture and was isoilerted by filtration. The crystals (fine powder) were dried under vacuum at room temperature. Example 5a Crystallization of Amlodipine Base to Form II 65 g The amlodipine free base of Example 1 was used in 25 ml dissolved in boiling toluene. This mixture slowly increased in 15 minutes 300 ml an n-hexane solution of 0-3 ° C with stirring. During the addition, the temperature of the n-hexane solution was kept below 3 ° C. The solid was filtered off and dried under vacuum at ambient temperature. 6.0 g of a white solid were obtained.

• Yield: 6.0 g (92%)
• HPLC: 99.3 area percent
• IR: corresponds to the form II as in 6 specified.
• FP: 138-140 ° C (uncorrected)
• DSC: insert at 100.12 ° C and insert at 140.39 ° C as in 7 specified.

Example 5b 5.0 g The free base of amlodipine was in 10 ml Ethyl acetate dissolved by heating with refluxing. Immediately after obtaining a clear solution, the mixture was forcibly cooled to -78 ° C (dry ice / acetone). There was no crystallization. However, the solution suddenly solidified outside the dry ice bath. The crystals (powder-like) were isolated by filtration and dried under vacuum at room temperature.

• IR: corresponds to the form II

Example 5c 2.0 g The free base of amlodipine was in 6 ml Ethyl acetate dissolved by heating with refluxing. The hot solution was filtered through hyflo to give a clear solution and added dropwise 100 ml Heptane was added with vigorous stirring at -78 ° C. The temperature of the heptane layer was kept below -70 ° C. The solid precipitate was collected by filtration and dried under vacuum at room temperature overnight.

• IR: corresponds to the form II.

Example 5d 2.5 g The free base of amlodipine was in 7 ml Ethyl acetate dissolved by heating with refluxing. The hot solution was filtered over Hyflo and added dropwise to an ice-cold (0 ° C) layer of 100 ml Heptane with vigorous stirring. The temperature of the heptane layer was maintained between 0 and 1 ° C. The precipitate was isolated by filtration and dried under vacuum at room temperature overnight.

• IR: corresponds to the form II

Example 5e 2.0 g The free base of amlodipine was in 10 ml Toluene dissolved by heating while refluxing. The hot solution was filtered over Hyflo and added dropwise to a precooled (0 ° C) layer of 100 ml Heptane with vigorous stirring. The temperature of the heptane layer was maintained between 0 and 1 ° C. The precipitate was isolated by filtration and dried under vacuum at room temperature overnight.

• IR: corresponds to the form II

Example 6a Synthesis of form II of the free base of amlodipine 100 ml of 40% methylamine in water and 12.6 g Phthalodipine was stirred for 16 h at 40-45 ° C. 150 ml Toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 50 ml Washed water. The mixture was reduced to about 75 ml and cooled to about -10 ° C on an ice / salt bath. A solid was formed which was filtered off and washed with 5 ml Toluene was washed. The solid product was dried in a vacuum oven.

• Yield: g (92%)
• HPLC: 98.8 area percent
• NMR: corresponds to the free base of amlodipine
• DSC: corresponds to form II of amlodipine base

Example 6b Synthesis of form II of the free base of amlodipine 100 ml of 40% methylamine in water and 12.6 g Phthalodipine FB.ADP.010710.01 was stirred at 40 ° C-45 ° C for 16 h. 150 ml Toluene was added and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was washed with 50 ml Washed water. The organic layer was reduced to 75 ml and cooled to -20 ° C. 75 ml n-heptane was added. A solid began to precipitate, which was filtered off. The solid was washed with 2 x 5 ml Washed n-heptane and dried in a vacuum oven. 7.9 g of a solid were obtained.

• Yield: 7.9 g (85%)
• HPLC: 98.8 area percent
• NMR: corresponds to the free base of amlodipine
• IR: corresponds to the form II
• DSC: corresponds to Form II

Example 7 Conversion of Form II of Amlodipine Base to Form I 1 g Form II of the amlodipine base was heated at 115 ° C for 4 h. The compound turned slightly yellow. 0.9 g of a solid were recovered.

• IR: corresponds to the free base of amlodipine
• DSC: corresponds to the form I

Example 8 Purification of amlodipine base via a salt 2.3 g of the crude amlodipine base were in 50 ml Toluene dissolved. 150 ml A 0.05 M HCl solution was added and the mixture was shaken vigorously. The layers were separated and became the aqueous layer 10 ml a 1 M NaOH solution. Solid formation started and the mixture was stirred at 3-5 ° C for 45 min. The solid was filtered off and washed with 2 x 5 ml Washed water. The solid was dried in a vacuum oven. 1.65 g of a solid were obtained.

• Yield: 1.65 g (72%)
• NMR: corresponds to the amlodipine base
• DSC: corresponds to form I of amlodipine base

Example 9 Stickiness Comparison

Tablets of the following composition were prepared on an EKO Excenter Press (Korsch): Amlodipine besylate tablets
47.5% microcrystalline cellulose (Avicell PH 112, FMC)
47.5 calcium sulfate dihydrate (Compactrol, Penwest Pharmaceuticals Co)
5.0% amlodipine besylate

Free base tablets of amlodipine
48.2% microcrystalline cellulose (Avicell PH 112, FMC)
48.2 calcium sulfate dihydrate (Compactrol, Penwest Pharmaceuticals Co)
3.67% amlodipine base (Reference Example 3)

Tablet properties:
Punch diameter: 20 mm
Tablet weight: 400 mg
Hardness: about 200 N

After 50 tablets, the tablet material was extracted from the punches using methanol and an ultrasonic bath. This procedure was repeated for runs of 100, 150, 200, 250 and 300 tablets. The extracts were measured spectrometrically together with amlodipine calibration samples. The amount of amlodipine in the samples was calculated from the calibration curve and the total amount of amlodipine extracted from both the upper and lower punches, and plotted against the produced tablet amount. A stickiness average was calculated from the slope of the regression line by shifting the y-section of the line through the zero point.
Average residue (stickiness) of amlodipine base: 0.55 μg ADP · cm ^-2 · tablet ¹
Average residue (stickiness) of amlodipine besylate: 1.16 μg ADP.cm ^-2 . Tablet ^-1

Example 10 Pharmaceutical tablet comprising the free base of amlodipine a) Calcium hydrogen phosphate / microcrystalline cellulose tablet composition

• – Die Amlodipinbase wurde durch ein 500-μm-Sieb gesiebt.
• – Die anderen Streckmittel wurden durch ein 850-μm-Sieb gesiebt.
• – Alle Streckmittel außer Magnesiumstearat wurden 15 min mit etwa 25 rpm in einem Freifallmischer gemischt.
• – Magnesiumstearat wurde zugegeben und das Pulvergemisch wurde weitere 5 min mit etwa 25 rpm gemischt.
• – 2,5-mg- und 10-mg-Tabletten wurden unter Verwendung einer Korsch EKO Excenter Press komprimiert.

Batches A, B, E and F of amlodipine base were prepared as follows:

• The amlodipine base was sieved through a 500 μm sieve.
• The other extenders were screened through an 850 μm sieve.
• All extenders except magnesium stearate were mixed for 15 minutes at about 25 rpm in a tumbler mixer.
• Magnesium stearate was added and the powder mixture was mixed for a further 5 minutes at about 25 rpm.
• 2.5 mg and 10 mg tablets were compressed using a Korsch EKO Excenter Press.

• – Die Amlodipinbase wurde gemahlen.
• – Die anderen Streckmittel wurden durch ein 850-μm-Sieb gesiebt.
• – Alle Streckmittel außer Magnesiumstearat wurden 15 min mit etwa 25 rpm in einem Freifallmischer gemischt.
• – Magnesiumstearat wurde zugegeben und das Pulvergemisch wurde weitere 5 min mit etwa 25 rpm gemischt.
• – 2,5-mg- und 10-mg-Tabletten wurden unter Verwendung einer Korsch EK Excenter Press komprimiert.

Batches C and D of amlodipine were prepared as follows:

• - The amlodipine base was ground.
• The other extenders were screened through an 850 μm sieve.
• All extenders except magnesium stearate were mixed for 15 minutes at about 25 rpm in a tumbler mixer.
• Magnesium stearate was added and the powder mixture was mixed for a further 5 minutes at about 25 rpm.
• 2.5 mg and 10 mg tablets were compressed using a Korsch EK Excenter Press.

None Problems were noted in the preparation of the above tablets.

b) microcrystalline cellulose based tablet composition

production method

• - The Amlodipine base was sieved through a 500 μm sieve.
• - ie other extenders were screened through an 850 μm sieve.
• - All Extender except Magnesium stearate and talc were stirred for 15 min at about 25 rpm in one Free fall mixer mixed.
• - magnesium stearate and talc were added and the powder mixture became more Mixed for 5 min at about 25 rpm.
• - 2.5 mg and 10 mg tablets were prepared using a Korsch EKO Excenter Press compressed.

c) dissolution profiles were using the blade device at a rotational speed of 75 rpm and a dissolution medium of 500 ml of 0.01 M hydrochloric acid recorded. The dissolution samples are analyzed by UV spectrophotometry at 237 nm. The average Resolution values (in % of the declared amount) are given in the table.

Example 1 Capsules of Amlodipine Free Base Composition:

Method:

• - The Amlodipine base was sieved through a 500 μm sieve.
• - The other extenders were screened through an 850 μm sieve.
• - All Extender except Magnesium stearate was stirred for 15 min at about 25 rpm in a tumbler mixer mixed.
• - magnesium stearate was added and the powder mixture was stirred for an additional 5 min Mixed 25 rpm.
• - gelatin capsules were filled with this powder mixture.

Claims (30)

A pharmaceutical tablet composition comprising an effective amount of the amlodipine free base and at least one pharmaceutically acceptable diluent wherein the amlodipine free base is either (i) the crystalline form II, (ii) amorphous or (iii) a mixture of the crystalline forms I and Form II and the formed tablet leaves an average residue on the tablet stamp of 0.7 μg cm ^-2 per tablet or less. A composition according to claim 1, wherein the extender Calcium phosphate is. A composition according to claim 1 or 2, wherein said Extender is microcrystalline cellulose. A composition according to claim 2, which further comprises microcrystalline Includes cellulose. A composition according to claim 4, wherein the calcium phosphate anhydrous calcium hydrogen phosphate. A composition according to any one of the preceding claims, wherein the tablet contains 1 to 100 mg of the free base of amlodipine. Crystalline free base of amlodipine Form II. Use of the free base of amlodipine in the Preparation of a medicament for treatment or prevention of hypertension, angina or decompensated heart failure. Method, comprising: Deprotect from N-protected Amlodipine with a deprotecting agent forming the free base of amlodipine, Failures of free base of amlodipine from a solution and Isolate the precipitated free base of amlodipine in solid form. The method of claim 9 wherein the solution is through the deprotection level is formed. The method of claim 10, wherein the solution is water contains. The method of any of claims 9-11, wherein the N-protected amlodipine is phthalodipine of formula (2a):

The method of claim 12, wherein the deprotecting agent aqueous Methylamine is. A method according to any one of the preceding claims 9-13, wherein the deprotection step in an aqueous solution or slurry he follows. The method of claim 14, further comprising extraction the free base of amlodipine in a water-immiscible solvent forming the solution includes. The method of claim 15, wherein said with water immiscible solvents Toluene is. A method according to any of claims 9-15, wherein the precipitate is a Crystallization stage is. The method of claim 17, wherein the crystallization the cooling the solution includes. The method of claim 18, wherein the crystallization additionally the evaporation of a part of the solvent out of the solution includes. A method according to any one of claims 17-19, wherein the crystallization the addition of a control solvent to the solution includes. Process according to any one of claims 17-20, wherein the crystallization at a temperature above 5 ° C begins. Process according to any one of claims 17-20, wherein the crystallization at a temperature of 5 ° C or less starts and the solution on a non-aqueous solvent based. A method according to any one of claims 9-22, wherein the isolated free base of amlodipine the crystalline free base of amlodipine Form I is. A method according to any one of claims 9-22, wherein the isolated free base of amlodipine the crystalline free base of amlodipine the form II is. A method according to any of claims 9-24, further comprising releasing isolated free base of amlodipine in a non-aqueous Cleaning Solvent and crystallizing the dissolved ones free base from the cleaning solvent to form purified crystalline free base of amlodipine includes. Process for purifying the free base of amlodipine, crystallizing the free base of amlodipine from one non-aqueous solvent includes. The method of claim 26, wherein the crystallization Crystals of the free base of amlodipine with an average Particle size of 150 up to 350 μm results. Population of particulate free base of amlodipine with an average particle size of at least 100 microns. The population of claim 28, wherein the particles Crystals are. The population of claim 29, wherein the average Particle size 150 to 350 microns.