Title:  Monohydrate lisinopril

United States Patent:  6,465,615

Issued:  October 15, 2002

Inventors:  Brown; John (Macclesfield, GB)

Assignee:  AstraZeneca AB (Sodertalje, SE)

Appl. No.:  950467

Filed:  September 10, 2001

The present invention relates to a novel monohydrate form of 1-(N² -[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline known under the generic name lisinopril. Further, the present invention also relates to the use of the novel monohydrate form of lisinopril for the treatment of hypertension and other cardiovascular diseases, pharmaceutical compositions containing it as well as processes for the preparation of the novel monohydrate form of lisinopril.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the lisinopril can be prepared in a novel monohydrate form, hereafter "monohydrate lisinopril form 2." Moreover, it has been found that monohydrate lisinopril form 2 possesses far greater solubility than lisinopril dihydrate (which is itself also crystalline). The more soluble monohydrate lisinopril form 2 is more suitable to certain formulations where quick solubility is desired, such as `fast melt` (melt-on-the-tongue type) formulations. It is an object of the present invention to provide monohydrate lisinopril form 2. It is a further object of the invention to provide mixtures of monohydrate lisinopril form 2 with other solid forms of lisinopril, such as lisinopril dihydrate. Another object of the present invention is to provide a process for the preparation of monohydrate lisinopril form 2, substantially free from other forms of lisinopril. Additionally it is an object of the present invention to provide pharmaceutical formulations comprising monohydrate lisinopril form 2.

Monohydrate lisinopril form 2 is a crystalline form exhibiting advantageous properties, such as being more soluble than crystalline lisinopril dihydrate. In addition, the novel monohydrate lisinopril form 2 particles are smaller and in a narrower size range (typically 5 .mu.m or less in edge length) than the dihydrate crystals. The more regular size and shape of the monohydrate lisinopril form 2 particles is expected to impart improved flow characteristics and so aid tablet manufacture compared to the long needle-like structures of lisinopril dihydrate. In addition, the use of a form of lisinopril having a reproducible particle size distribution may obviate the need for milling prior to capsulation or tabletting. ZESTRIL.RTM. is conventionally manufactured using milling, wet granulation and tabletting. Obviating the need for a milling step could speed up manufacture and reduce costs.

Tablet manufacture by direct compression, as opposed to wet granulation, is prone to size-based segregation of the drug substance from the remaining excipients, leading to a non-uniform mix and to tablets of variable drug content. Segregation is exacerbated by large differences in the particle size of the drug substance and the excipients. The more regular particle size of the monohydrate lisinopril form 2 compared to the dihydrate material would be expected to be prone to less segregation.

Thus, according to a first aspect of the invention there is provided monohydrate lisinopril form 2 characterized in having strong or very strong X-ray diffraction peaks at d-spacings of about 12.0 and 11.5 and additionally characterized by diffraction peaks at 7.6, 6.5, 5.4, 4.59, 4.23, 4.16, 4.09, and 3.91 .ANG.. The XRPD pattern of monohydrate lisinopril form 2 is further characterized by the lack of X-ray diffraction peaks at d-spacings of about 15.2, 8.1, 6.3, 5.69 and 4.72 .ANG., which are present in the XRPD pattern of monohydrate lisinopril form 1 disclosed by Ip et al.

Monohydrate lisinopril form 2 can also be identified by the criterion that melt onset occurs at about 167^oC. and the peak of the endotherm occurs at about 177^oC. when measured by DSC at a heating rate of 10^oC./min in a pierced pan in air.

Monohydrate lisinopril form 2 can also be identified by an IR absorption spectrum having bands at about 3637, 3440, 1648, 1617, 1564, 1451, 1443, 1373, 1205, 759 and 705 cm^-1, and the absence of absorption bands at about 3407 and 3293 cm^-1.

Monohydrate lisinopril form 2 can also be identified by a Raman spectrum having bands at about 3061, 3050, 3042, 2988, 2937, 2900, 1651, 1600, 1580, 1375, 1196, 1001 and 834 cm^-1, and the absence of bands at about 3070, 2966, 2870, 1604 and 1585 cm^-1.

One routine method of differentiating monohydrate lisinopril from 2 from other crystalline and non-crystalline forms of lisinopril is X-ray powder diffraction (XRPD). The XRPD pattern of monohydrate lisinopril form 2, as illustrated in FIG. 2 and with reference to Table 2, can be seen to exhibit additional intensity on some peaks, but also to lack a number of peaks found in the monohydrate disclosed in Ip et al. In the first instance, a monohydrate lisinopril, either of form 1 or form 2, can be differentiated from lisinopril dihydrate, or mixtures of monohydrate and dihydrate lisinopril, by determining the water content. A lisinopril monohydrate contains 4.08%, by weight, of water while lisinopril dihydrate contains 8.16%, by weight, of water. Standard methods of determination of water content are Karl-Fischer titration and Thermogravimetric Analysis (TGA).

The various physicochemical properties of the monohydrate lisinopril form 2 were identified according to the methods employed in the Examples. It should be understood that these are experimental values and spectrums, which are provided for reference purposes. Whether or not a particular compound is monohydrate lisinopril form 2, should not be determined according to the precise values determined in the Examples. It will be readily understood by those skilled in the art that that such experimental values and spectrums may involve experimental errors due to factors including the measuring apparatus, the process, experimental conditions etc. The various techniques identified and approximate figures listed are however sufficient to enable the person skilled in the art to determine whether or not a particular compound is monohydrate lisinopril form 2 according to the present invention.

Monohydrate lisinopril form 2, or the presence of some monohydrate lisinopril form 2, can be distinguished from other crystalline and non-crystalline forms of lisinopril, using X-ray powder diffraction, Raman spectroscopy, differential scanning calorimetry, solid state nuclear magnetic resonance spectra (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art. Furthermore, monohydrate lisinopril form 2 is much more soluble than crystalline lisinopril dihydrate, providing another means of discriminating between the dihydrate and monohydrate lisinopril forms, or detecting an amount of monohydrate lisinopril form 2 within a lisinopril dihydrate preparation.

As noted above, a routine method of differentiating monohydrate lisinopril from 2 from other crystalline and non-crystalline forms of lisinopril is X-ray powder diffraction (XRPD), optionally combined with analysis of water content.

Another method of distinguishing physical forms, such as dihydrate lisinopril and monohydrate lisinopril form 2, is ¹³ C solid state NMR spectra (ssNMR) acquired with cross polarization, magic angle spinning and high power proton decoupling. The isotropic chemical shifts (peak positions) measured in solid-state NMR spectra are not only a function of the molecule's atomic connectivity, but also of molecular conformation and inter- and intra-molecular interactions. Thus different peak positions may be observed for different physical forms.

In one embodiment of the invention, monohydrate lisinopril form 2 is substantially free from other forms of lisinopril. Substantially free from other forms of lisinopril shall be understood to mean that the composition comprising monohydrate lisinopril form 2 contains less than 50%, preferably less than 25%, more preferably less than 10% and still more preferably less than 5% of any other forms of lisinopril, e.g dihydrate lisinopril or amorphous lisinopril.

In a further embodiment monohydrate lisinopril form 2 is in increasing order of preference, at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% and 100% pure. The presence of organic contaminants can be detected by HPLC. Purity can be measured using a solid-state method such as XRPD or ssNMR.

It will be appreciated however, that because of the enhanced solubility property of monohydrate lisinopril form 2, mixtures comprising substantially dihydrate or other solid forms of lisinopril with monohydrate lisinopril, depending on the amount of form 2 monohydrate product present, may also possess varying degrees of increased solubility. Such mixtures comprising monohydrate lisinopril can be prepared, for example, by mixing monohydrate lisinopril form 2 prepared according to the present invention with other solid forms of lisinopril, such as crystalline dihydrate form, prepared according to prior art methods. A mixture might also be prepared if the manufacturing process is incomplete, or incorporates steps that allow or cause monohydrate product to be formed.

Thus, the present invention also relates to mixtures comprising monohydrate lisinopril form 2 in admixture with other solid forms of lisinopril. Such mixtures comprising monohydrate lisinopril form 2 include for instance mixtures containing a detectable amount of monohydrate lisinopril form 2, which is 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% (by weight), of the total lisinopril.

Examples of other solid forms of lisinopril include, but are not limited to, dihydrate lisinopril and monohydrate lisinopril form 1.

A detectable amount of monohydrate lisinopril form 2 is an amount that can be detected using conventional techniques, such as FT-IR, Raman spectroscopy, XRPD, TGA, DSC and the like.

Numerous techniques can be employed to detect a particular form of a compound within a mixture. The limits of detection of a particular form in a mixture with another form, e.g., monohydrate form 2 mixed with dihydrate, is as follows: by XRPD it is reported to be approximately 5% according to Hancock and Zografi (J. Pharm. Sci., 86:1-12, 1997) and approximately 2% according to Surana and Suryanarayanan (Powder Diffraction, 15:2-6, 2000). The limits of detection by solution calorimetry is reported to be approximately 1% according Hogan and Buckton (International Journal of Pharmaceutics, 207:57-64, 2000). The limits of detection by solid state NMR is reported to be approximately 5-10% according to Saindonet al., (Pharmaceutical Research, 10:197-203,1993). The limits of detection by near infra red spectroscopy is reported to be approximately 2-5% according to Blanco and Villar (Analyst, 125:2311-2314, 2000). The limits of detection by Modulated Differential Scanning Calorimetry (MDSC) is reported to be approximately 6% according to Saklatvala et al., (International Journal of Pharmaceutics, 192:55-62, 1999). The limits of detection by FT-Raman spectroscopy is reported to be approximately 2% according to Taylor and Zografi (Pharm. Res. 15:755-761, 1998).

Monohydrate lisinopril generically can be prepared by crystallization from alcohol solutions. A suitable method for preparing monohydrate lisinopril form 2 is to dissolve crystalline lisinopril dihydrate, or any other form of lisinopril in water and add an organic water miscible solvent, such as isobutanol, followed by precipitation, filtration and drying.

According to one aspect of the invention there is provided a process for the preparation of monohydrate lisinopril form 2 comprising the steps of:

a) dissolving lisinopril of any form, or a mixture of forms of lisinopril in a aqueous solvent;

b) adding a water miscible organic solvent, such as isobutanol;

c) allowing a precipitate to form; and,

d) isolating and drying the precipitate.

According to one aspect of the invention there is provided a process for the preparation of monohydrate lisinopril fcomprising the steps of:

a) dissolving lisinopril of any form, or a mixture of lisinopril of any form in water;

b) adding isobutanol;

c) maintaining the product of (b) in a condition under in crystalline lisinopril forms and isolating the crystals; and,

d) drying the crystals of (c), preferably under vacuum at approximately 80^oC.

By the term `any form` we include, solvated and desolvated forms, crystalline forms and other non-crystalline forms.

Mixing, e.g. agitation or stirring, is preferable during both the dissolving step and the precipitation step. The precipitation should continue for a period to ensure that monohydrate product formation is as complete as possible, e.g. up to 15 hours, preferably, 1-8 hours.

The product may be separated from the solution, e.g. by filtration or centrifugation. The product can be dried to a constant weight, e.g. at 80^oC., and preferably at reduced pressure, for, e.g. 10 to 48 hours. For storage, the monohydrate product is preferably kept at 25^oC., 60%RH (ambient conditions).

In a further aspect, the invention provides a compound obtainable by a process or method as described above.

`Zestril` has received regulatory approval for use in the following indications:

Hypertension

`Zestril` is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.

Congestive Heart Failure

`Zestril` is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis. High doses reduce the risk of the combined outcomes of mortality and hospitalization.

Acute Myocardial Infarction

`Zestril` is indicated for the treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.

Renal And Retinal Complications of Diabetes Mellitus

In normotensive insulin-dependent and hypertensive non-insulin-dependent diabetes mellitus patients who have incipient nephropathy characterised by microalbuminuria, `Zestril` reduces urinary albumin excretion rate. `Zestril` reduces the risk of progression of retinopathy in normotensive insulin-dependent diabetes mellitus patients.

According to the invention there is further provided a pharmaceutical composition comprising monohydrate lisinopril form 2, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients. Compositions comprising other therapeutic ingredients are especially of interest in the treatment of hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.

The invention also provides the use of monohydrate lisinopril form 2 in the manufacture of a medicament for use in the treatment of a cardiovascular related condition, and in particular, a method of treating a hypertensive or congestive heart failure condition which method comprises administering the medicament to a subject suffering from said condition a therapeutically effective amount of lisinopril.

The invention also provides the use of monohydrate lisinopril form 2 in treating hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.

Any suitable route of administration may be employed for providing the patient with an effective dosage of drug comprising monohydrate lisinopril form 2 according to the invention. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric-coated capsules and/or tablets, capsules and/or tablets containing enteric-coated pellets of lisinopril. In all dosage forms monohydrate lisinopril can be mixed or combined with other suitable constituents. One preferred route of administration is peroral using fast melt tablets.

The compositions of the invention comprise the compound of the invention. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.

In view of the enhanced solubility that monohydrate lisinopril form 2 has compared to crystalline lisinopril dihydrate, compositions wherein some, but preferably a substantial amount, of the total amount of the lisinopril is monohydrate (i.e. >20%), can be prepared as a `fast melt` tablet and/or formulation.

A fast melt tablet is defined as a tablet dosage form that is intended to disintegrate in the patient's mouth without the need for chewing or water. In one embodiment, the fast melt tablet disintegrates in approximately one minute. If the drug and tablet excipients are sufficiently soluble, the fast melt tablet dissolves to a complete solution before the patient swallows.

Several advantages of fast melt tablets over conventional oral tablets and liquids may exist. Patient compliance may improve because of ease of swallowing, lack of need for water, and taste-masking and improved accuracy of dosage. Patient populations that may benefit the most include geriatric patients, pediatric patients and patient who cannot swallow or have difficulty in swallowing. A fast melt tablet would also benefit patients with congestive heart failure who tend to retain fluid, and therefore are treated with fluid intake restriction. The fluid used to take their medications are included in the amount of fluid that they are prescribed per day (which may be as little as 500 ml), so a fast melt tablet that can be taken without fluid would benefit these patients.

Fast melt tablets are manufactured by a variety of tablet technologies including wet granulation, direct compression and freeze-drying (see for example: Corveleyn and Remon, International Journal of Pharmaceutics, (1997) 152:215-225).

For a general review on fast melt technology please consult, Habib et al., (Critical Reviews in Therapeutic Drug Carrier Systems, 17(1):61-72, 2000).

According to a further aspect of the invention there is provided a fast melt tablet formulation comprising monohydrate lisinopril form 2.

Crystalline lisinopril dihydrate is soluble in water and goes into solution in the gastrointestinal tract rapidly after ingestion. This is demonstrated by the dissolution of the current marketed Zestril.RTM. tablets in which typically greater than 90% of the dose is dissolved within 15 minutes. Once in solution, absorption is limited by the physicochemical characteristics of the compound, its ability to cross the gastrointestinal mucosa and enter into the blood stream and transit time of the gut. A form that would go into solution more rapidly would only affect the first step, however. Thus, despite the enhanced solubility that a lisinopril formulation comprising monohydrate lisinopril form 2 would be expected to have, because solubility is not a limiting step in the rate and extent of absorption of lisinopril, it is unexpected that this would affect the bio-availability or the clinical benefits of lisinopril.

In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of monohydrate lisinopril form 2 in any given case will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight, and response of the individual patient.

In general, a suitable oral dosage form may cover a dose range from 0.5 mg to 150 mg total daily dose, administered in one single dose or in multiple, such as, equally divided doses. A preferred dosage range is from 1 mg to 60 mg.

Combination therapies comprising monohydrate lisinopril form 2 and other active ingredients in separate dosage forms, or in one fixed dosage form, may also be used. Examples of such active ingredients include anti-bacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates, prokinetic agents, other antihypertensive agents, diuretics, digitalis, thrombolytics, aspirin and beta-blockers.

Claim 1 of 11 Claims

What is claimed is:

1. A particulate crystalline lisinopril monohydrate formed by the process consisting of:

(a) dissolving 1-(N² -[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline ("lisinopril") in water to form a solution;

(b) adding isobutanol to the solution of step (a) in an amount and under conditions effective to induce crystallisation of the lisinopril monohydrate;

(c) isolating the crystals formed in step (b);

(d) drying the crystals at a temperature not to exceed 80^oC. for a time and under conditions effective to produce particulate crystalline lisinopril monohydrate; and

(e) recovering the particulate crystalline lisinopril monohydrate.
 

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