FR2924223A1 - PROCESS FOR DETERMINING THE POLYMORPH PURITY OF MANIDIPINE DICHLORHYDRATE. - Google Patents

Abstract

A method for determining the polymorphic purity of beta polymorphic manidipine dihydrochloride in a pharmaceutical tablet using Raman spectral information, comprising the steps of: i) preparing a series of known samples, each of known samples comprising a quantity of polymorph beta and a quantity of polymorph alpha, in which, in each of the known samples, the total amount of the compounds remains the same while their ratio is modified, ii) acquire the Raman spectra of the various known samples, iii) select one or more wavelength signals for each form so that the spectral differences that appear in each of the known samples are essentially appreciable and so that the signals of the excipients do not interfere iv) perform a statistical analysis of the spectral data of the series of known samples, v) collect data es spectrum of a sample comprising the polymorphic manidipine dihydrochloride beta with an unknown polymorph purity; andvi) calculating the polymorphic purity of the beta polymorph.

Description

METHOD FOR DETERMINING THE POLYMORPH PURITY OF MANIDIPINE DICHLORHYDRATE

Field of the Invention The present invention generally relates to a method for determining polymorphic purity. More specifically, the present invention refers to a method for determining the polymorphic purity of polymorphic manidipine dihydrochloride in a solid dosage pharmaceutical form using Raman spectroscopy information.

BACKGROUND OF THE INVENTION The ability to be in different crystalline structures is known as polymorphism and is known to occur in many organic compounds. These different crystalline forms are known as polymorphic or polymorphic modifications and are made in their crystalline state. While the polymorphic modifications have the same chemical composition, they differ in packaging, geometric disposition, and other descriptive properties of the crystalline solid state.

Polymorphism is an important phenomenon to consider in pharmaceutical development, since different polymorphs have different physical properties in the solid state, which in turn can influence the physical stability, the dissolution properties and therefore the bioavailability of drugs. It is therefore essential to evaluate the polymorphism to be able to select the crystalline form of a drug most suitable for its stability and bioavailability. Furthermore, it is well known that during the preparation procedures, such as drying, grinding, compression of solid dosage forms such as tablets, polymorphic transformations can take place (also known as transitions) with the formation of significant amounts of the undesirable crystalline form.

These transitions may be responsible for phenomena such as post-compression curing of the tablets and, since different polymorphs may also have different solubilities and different hydrolysis rates, they may significantly influence both the dissolution properties and the chemical stability of the drug. In light of all these considerations, it is very important to measure whether the polymorphic purity of the chosen crystalline form of the drug is maintained in the final solid dosage form. Methyl (1,4-dihydro) -2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid dihydrochyridine dihydrochloride is a calcium channel blocking dihydropyridine dihydrochloride useful for the treatment of hypertension, described in US Pat. for the first time in European patent EP 94195. Manidipine exists in two polymorphic forms known as the α-form and the R-form. The latter, the preparation of which is described in patent JP 1284729, is used for the manufacture of tablets. currently on the market since form a is less stable. In order to distinguish the two crystalline forms, the most widely used analytical techniques are IR spectroscopy, X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). However, these techniques can not be used for the quantitative determination of the polymorphic purity of the manidipine dihydrochloride polymorph in solid dosage forms, since its signals and / or its melting peak are covered by those of the commonly used excipients. preparation of tablets. Thus, it is necessary to find a method for determining polymorphic purity of polymorphic manidipine dihydrochloride in a solid oral dosage form such as a tablet. In particular, it would be very advantageous to provide a fast, specific and accurate method and a corresponding apparatus for identifying the presence of undesirable crystalline polymorph in an amount of less than or equal to 15% in tablets containing polymorphic crystalline manidipine dihydrochloride 13.

Summary of the Invention The invention relates to a method for determining the polymorphic purity of polymorphic manidipine dihydrochloride 13 in a pharmaceutical tablet, using Raman spectral information, comprising the steps of: i) preparing a series of known samples each of them comprising an amount of polymorph 13 and a quantity of polymorph a, wherein in each of the known samples the total amount of the compounds remains the same while their ratio is changed; ii) record the Raman spectra of the different known samples; iii) selecting one or more wavelength signals for each shape so that the spectral differences that are generated in each of the known samples are substantially appreciable and the signals of the excipients do not interfere; iv) performing partial least squares regression analysis of the spectral data of the series of known samples; v) collecting the spectral data of a sample comprising polymorphic manidipine dihydrochloride 13 of unknown polymorphic purity; and vi) calculating the polymorphic purity of polymorph 13. The invention also relates to a process for the manufacture of pharmaceutical tablets comprising polymorph 13 manidipine dihydrochloride as an active ingredient with a polymorphic purity of 85% or more based on of the total amount of the active ingredient, said process comprising the steps of: a) mixing the manidipine dihydrochloride with suitable excipients selected from classes of fillers, binders and disintegrants; b) optionally, granulating the resulting mixture with water and drying, c) adding a slip agent to the mixture; d) compress the mixture by obtaining tablets; e) optionally, distribute the tablets in a wafer package; and f) determining the polymorphic purity of the polymorphic manidipine dihydrochloride in the final tablets using the method described herein.

The invention also relates to pharmaceutical tablets comprising polymorphic manidipine dihydrochloride as an active ingredient having a polymorphic purity equal to or greater than 85% based on the total amount of the active ingredient, wherein the polymorphic purity of the Active ingredient was determined by the process described above.

Brief Description of the Figures Figure 1 shows the typical Raman spectrum of the form manidipine dihydrochloride as a starting material. Figure 2 shows the typical Raman spectrum of manidipine dihydrochloride of Form a as starting material. Figure 4 shows the Raman spectrum of a tablet comprising 10 mg of form manidipine dihydrochloride as the active ingredient and the following excipients: lactose having a particle size of 200 mesh, starch, Klucel LF, LHPCulH 11, riboflavin and magnesium stearate ( Iperten tablets). Figure 5 shows the Raman spectrum of a tablet comprising 10 mg of form a manidipine dihydrochloride as an active ingredient and the following excipients: lactose having a particle size of 200 mesh, starch, Klucel LF, LHPCuLH 11, riboflavin and stearate. magnesium. Figure 3 shows the Raman spectra obtained in the 1800 x 1400 cm -1 spectral region for a series of tablet samples comprising fixed amounts of manidipine dihydrochloride of form and form a in different ratios and the following excipients: lactose having a particle size of 200 mesh, starch, Klucel LF, LiHPCuLH 11, riboflavin and magnesium stearate.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for determining polymorphic purity in a pharmaceutical tablet comprising polymorphic manidipine dihydrochloride, the polymorphic purity of which is unknown. The method uses Raman spectral information and the spectra are recorded simply by inserting the sample into the cell.

Any Fourier Transform Raman (FT) apparatus can be advantageously used, for example commercially available devices from PerkinuElmer, MA, USA, Kaiser Optical Systems, MI, USA, Jasco, Tokyo, Japan, and Bruker. , Ettlinger, Germany. The Raman spectrum of manidipine dihydrochloride as a raw material is shown in Figure 1. It shows the following major peaks in the range 3500 ± 700 cm -1 (1 cm accuracy): 3340 cm -1 (w) ; 3120-2820 (s); 1719 (m); 1651 (vs); 1622 (m); 1578 (m); 1532 (m); 1480 (m); 1438 (m), 1348 (vs); 1004 (s); The Raman spectrum of manidipine dihydrochloride of a form as a raw material is shown in Figure 2. It shows the following major peaks in the range 3500 ± 700 cm (accuracy 1 cm - 1): 3370 cm -1 (w). ); 3130-2800 (s); 1669 (s); 1657 (s); 1626 (m); 1603 (m); 1582 (m); 1526 (w); 1478 (w); 1440 (w); 1342 (vs); 1004 (s). As a result, the FTuraman spectra of tablets comprising manidipine dihydrochloride in the α-form and, respectively, in admixture with excipients do not show signals due to the excipients in the spectral region of between 1800 and 1400 cm -1. 30 * Legend: vs = very strong; s = strong; m = average; In particular, form manidipine dihydrochloride in tablets comprising lactose excipients having a particle size of 200 mesh, starch, Klucel LF, LHHPCULH 11, riboflavin and magnesium stearate, shows the following major peaks in the region 1800 ± 1400 cm. -1 (precision 1 cm1): 1719 cm -1; 1651; 1622; 1578; 1532; 1480; 1438.

On the contrary, the form a shows the following principal peaks: 1669 cm -1; 1626; 1603; 1582; 1526; 1478; 1440. The spectra of the two polymorphs in this spectral region appear distinctly distinct, with obvious differences in wavelength and band intensity, and therefore, their signals can be used to determine their relative quantities, and therefore In a particular embodiment, the signals at 1719 cm -1 and 1669 cm -1 can be used with diagnostic markers and their ratio is used to determine the relative amounts of the two forms. In particular, the method for determining the polymorphic purity according to the invention comprises the following steps. First, a series of samples, preferably in tablet form, are prepared in which each of the samples comprises prefixed amounts of form manidipine dihydrochloride and form a manidipine dihydrochloride.

In each of the samples, the total amount of the compounds remains the same while the ratio between them is changed. The total amount of the two compounds may vary depending on the capacity of the sample cell of the FTiraman instrument. Preferably, a total amount of 10 mg or 20 mg is used. From 5 to 20 samples can be used in which the ratio between the form (3 and the form a can vary between 99: 1 and 1: 99. For example, 10 samples in which the ratio varies between 95: 5 and 5: 95. In a second step, the Raman spectra of the various known samples are acquired and one or more signals are chosen for each form whose wavelengths show a significant spectral difference in each of the known samples and show no overlap with the signals of the excipients present in the tablet.

In a third step, a least squares regression analysis of the spectral data of the series of known samples is performed using the ratio of the heights or areas of the signals that are diagnostic markers for each form.

Alternatively, other chemometric methods may be advantageously employed, such as multivariate regression analysis or a particular multivariate regression model known as partial least squares regression, both of which are widely used to relate the spectral data to known compositional changes. A summary of chemometric methods can be found in R. G. Brereton, Chemometrics, Data Analysis for the Laboratory and Chemical Plant, Wiley & Sons, 2003, and in J. Adams, Chemometrics In Analytical Spectroscopy, 2nd Ed. Royal Society of Chemistry (2004). Finally, the spectral data of a sample containing manidipine dihydrochloride of form (3) having an unknown polymorphic purity in an amount equal to that of the total amount in each of the known samples are acquired and the unknown polymorphic purity of the polymorph is calculated ( 3 in the sample Advantageously, the sample comprising form (3) manidipine dihydrochloride having an unknown polymorphic purity is in the form of a pharmaceutical tablet for oral use, comprising from 5 to 40 mg of manidipine dihydrochloride (3). in admixture with one or more pharmaceutically acceptable excipients such as those described, for example, in Remington's Pharmaceutical Sciences Handbook, Mack Pub., NY, USA.

More preferably, the sample is in the form of a tablet comprising 10 to 20 mg of R-form manidipine dihydrochloride in admixture with one or more pharmaceutically acceptable excipients selected from classes of fillers such as lactose, phosphates, lubricants such as magnesium stearate, sodium stearyl fumarate, polyethylene glycols and lubricants such as colloidal silica, binders such as cellulose, disintegrants such as crosprovidone, sodium starch glycolate, croscarmellose, starch, hydroxypropylcellulose.

Excipients such as sweeteners, flavorings, dyes and other commonly used agents may also be added to the formulation. More preferably, the sample is a tablet comprising 10 mg or 20 mg form manidipine dihydrochloride and sold under the brand name Iperten having, according to the dosage of the active ingredient, the following formulation:

Table IPERTEN (10 mg) Quantity IPERTEN (20 mg) Unit Quantity (mg) (mg) Manidipine * 2HC1 10.00 Manidipine * 2HC1 20.00 Lactose 200 mesh 119.61 Lactose 200 mesh 132.30 Starch 17.00 Starch 20.00 Hydroxypropylcellulose 6.50 Hydroxypropylcellulose 6.50 (Klucel LF) (Klucel LF) Hydroxypropylcellulose 17.00 Hydroxypropylcellulose 20.00 (LùHPCùLH 11) (LùHPCùLH 11) Riboflavin 0.04 Riboflavin 0.20 Mg 0.85 stearate Mg Stearate 1.00 Total Quantity 170.00 Total Quantity 200.00 The tablets may be dispensed in packages commonly made of polyvinyl chloride (PVC) or polyvinylidene (PVD) multilayer films and sealed with an aluminum strip. The invention also relates to a process for the manufacture of pharmaceutical tablets comprising polymorphic manidipine dihydrochloride as an active ingredient having a polymorphic purity equal to or greater than 85% based on the total amount of the active ingredient, said process comprising: a step of determining the polymorphic purity of the polymorphic manidipine dihydrochloride in the final tablets by means of Raman spectroscopy. Advantageously, this process comprises the steps of: a) mixing the manidipine dihydrochloride with suitable excipients selected from the classes of fillers, binders and disintegrants; b) optionally, granulating the resulting mixture with water and drying it; c) adding a slip agent to the mixture and optionally a lubricant; d) compress the mixture by obtaining tablets; e) optionally, distribute the tablets in a wafer package; and f) determining the polymorphic purity of the polymorphic manidipine dihydrochloride (3 in the final tablets by means of Raman spectral information.) The granulation step can be carried out in a suitable apparatus such as a high shear mixer, such as the Diosna device or a fluidized bed device The spectral information is analyzed with ad hoc methodical software.

In one embodiment of the invention, after the preparation of the tablets according to the procedure outlined above in online production, samples of these tablets may be transported to a laboratory equipped with a FTiraman instrument where purity is determined. polymorph of the active ingredient by the method of the invention. Alternatively, the FTiraman instrument is located offline at the end of the production line. In a preferred embodiment, the polymorphic purity of the active ingredient in the final tablets is determined online. This analysis system is particularly suitable for industrial scale applications since it is continuous, fast and minimizes the possibility that sampling may influence the analytical results.

Online analysis can be performed by passing the tablets directly under the laser beam of the Raman instrument using a conveyor belt. The analysis may be performed before the tablets are dispensed in blister pack or after packaging. Advantageously, with the application of the method of the invention, it is possible to detect the manidipine dihydrochloride in form with a polymorphic purity equal to or greater than 85%, preferably equal to or greater than 90%, more preferably greater than 95% w / w based on the total amount of the active ingredient. The following example illustrates the invention better.

EXAMPLE Evaluation Evaluation of the Polymorphic Purity of Polymorph Beta Manidipine Dihydrochloride in IPERTEN 10 MG Tablets In order to explore the possibility of identifying the presence of undesirable polymorph in Iperten tablets, a series of was performed on tablets comprising a polymorph a and a polymorph in different mixing ratios with a mixture of excipients which reflect the actual composition of Iperten tablets 10 mg (placebo). Materials Manidipine dihydrochloride in form was obtained from Takeda Chemical Industries. DSC: 217 ° C; IR (KBr): 1719 cm -1, 1652, 1622, 1533, 1480, 1458, 1438. Manidipine dihydrochloride in the form of oc was obtained by recrystallization of a saturated solution (about 25 g / l) of form in absolute ethanol, placed to settle for 10 minutes. The hot solution was filtered through a paper filter into a funnel and allowed to cool spontaneously at room temperature and finally kept at 4 ° C overnight. The yellow suspension was filtered at the pump and dried under a stream of air for 30 minutes. The solid was recovered and further dried under vacuum over P2O5 for 12 h. DSC: 163 ° C; IR (KBr): 1670 cm -1, 1656, 1526, 1478, 1456, 1436.

The placebo which reflects the actual composition of the Iperten tablets was separated by a mixture of lactose having a particle size of 200 mesh, starch, Klucel LF, LiHPClH11, riboflavin and magnesium stearate in ratios of weight of 74.6: 10.7: 3.5: 10.7: 0.02: 0.48, respectively.

Instrumentation A Perkin Elmer FTùRaman 2000R spectrophotometer, equipped with INGAAS detector, RAMDPY1 source and QUARTZ beam splitter. The spectra were acquired under the following conditions: • Scanning range: 4000 to 200 cm-1 • Number of accumulations: 64 • Resolution: 4 cm-1 • Gain: 1 • Apodization: strong • BùStop dimension: 21 mm • JùStop dimension : 8 mm • Phase correction: Magn

Preparation of Physical Mixtures of Manidipine * 2HC1a and 13 Nine physical mixtures were prepared (MP 1ù9) of both manidipine polymorphs * 2 HC1: PM1: 10.6 mg form a + 0 mg form + 159.7 mg placebo; PM2: 9.8 mg PM3: 8.6 mg PM4: 5.3 mg PM5: 2.7 mg PM6: 2.0 mg PM7: 1.2 mg PM8: 0.6 mg form a + 0, 8 mg form + 159.2 mg placebo form a + 1.7 mg form + 159.2 mg placebo form a + 5.0 mg form + 160.6 mg placebo form a + 7.6 mg form + 160.2 mg placebo form a + 7.9 mg form + 158.8 mg placebo form a + 9.7 mg form + 159.4 mg placebo; form a + 10.3 mg form + 157.4 mg placebo; 30 PM9: 0 mg form a + 11.0 mg form + 162.2 mg placebo. Each physical mixture was then compressed.

Implementation of the process FIGS. 1 and 2 show the typical Raman spectra respectively of the manidipine * HC1 of form and of form a as starting materials.

Figures 4 and 5 show against the spectra of the corresponding tablets. In searching for a band to be considered diagnostic for the polymorph a, the 1669 cm -1 band, which is outside the region of the manidipine R signals, was selected.

In Figure 3, a superposition of the Raman spectra in the 1800 x 1400 cm -1 spectral region is indicated for the tablet-shaped samples obtained from the physical mixtures PM1, PM4, PM6, PM7 and PM9. As can be seen, the signal at 1669 cm -1 can be clearly distinguished in all samples analyzed.

A least squares regression analysis of the spectral data of the PM1UPM9 sample series was performed, using the ratio between the signal areas at 1719 cm -1 for the form and 1669 cm -1 for the form a, then the Raman spectrum of a 10 mg Iperten tablet comprising form manidipine dihydrochloride having an unknown polymorphic purity.

Claims (13)

claims A method for determining the polymorphic purity of polymorph [3] manidipine dihydrochloride in a pharmaceutical tablet, using Raman spectral information, comprising the steps of: i) preparing a series of known samples, each of known samples comprising a a quantity of polymorph 3 and a quantity of polymorph a, in which, in each of the known samples, the total amount of the compounds remains the same while their ratio is changed; ii) acquire the Raman spectra of the different known samples; iii) selecting one or more wave length signals for each shape so that the spectral differences that occur in each of the known samples are more appreciable and so that the signals of the excipients do not interfere; iv) perform a statistical analysis of the spectral data of the series of known samples; v) collecting the spectral data of a sample comprising polymorphic manidipine dihydrochloride (3 having unknown polymorphic purity; and vi) calculating the polymorphic purity of the polymorph [3. The process according to claim 1, wherein the sample comprising polymorphic manidipine dihydrochloride 13 having unknown polymorphic purity is in tablet form. The method of claim 1, wherein the tablet comprises polymorphous manidipine dihydrochloride [3] in a dosage amount of between 5 and 40 mg. 4. The method of claim 3, wherein the tablet comprises polymorphous manidipine dihydrochloride [3] in a dosage amount of 10 mg. 2924223 X14 The method of claim 3, wherein the tablet comprises polymorphous manidipine dihydrochloride in a dosage amount of 20 mg. The method according to any one of claims 3 to 5 wherein the tablet comprises one or more conventional pharmaceutically acceptable excipients such as lactose, starch and magnesium stearate. 7. A process according to claim 6, wherein the tablet comprises the following excipients: lactose having a particle size of 200 mesh, starch, Klucel LF, LiHPCuLH II, riboflavin and magnesium stearate. The method of claim 7, wherein the excipients are in a weight ratio of 74.6: 10.7: 3.5: 10.7: 0.02: 0.48, respectively. A process for producing pharmaceutical tablets comprising polymorphic manidipine dihydrochloride as an active ingredient having a polymorphic purity equal to or greater than 85% based on the total amount of the active ingredient, said process comprising the steps of: ) mixing the manidipine dihydrochloride with the suitable excipients selected from the classes of fillers, binders, and disintegrants; b) optionally granulating the resulting mixture with water and drying it; c) adding a slip agent to the mixture; d) compress the mixture by obtaining tablets; e) optionally, dispensing the tablets in a wafer package, characterized in that it comprises a step f) of determining the polymorphic purity of the polymorphic manidipine dihydrochloride f3 in the final tablets using the method of claim 1. The method of claim 9 wherein step f) is performed online. A pharmaceutical tablet obtained by the manufacturing method of claim 9, comprising polymorphous manidipine dihydrochloride R as an active ingredient having a polymorphic purity of 85% or more based on the total amount of the active ingredient. The pharmaceutical tablet according to claim 11 wherein the polymorphic purity is equal to or greater than 90%. The pharmaceutical tablet of claim 12 wherein the polymorphic purity is greater than 95%.