Patent Application
20080200680
The present invention relates to methods for preparing solid dose preparations comprising Zolpidem hemitartrate, and more particularly the invention relates to converting Zolpidem hemitartrate polymorphs into a desired polymorph in the process of making tablets.
Zolpidem, a known pharmaceutical that possesses anxiolytic, sedative, and hypnotic properties and which is F.D.A. approved for short-term treatment of insomnia, has the following structural formula:
Many pharmaceutical solids, including Zolpidem, exist in different physical forms, e.g., crystalline or amorphous. Polymorphism refers to the occurrence of different crystalline forms of the same drug substance. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystalline solids containing amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates.
It is known in the art that the crystal forms (polymorphs) of a drug molecule can be made or transformed under different environmental conditions, typically in contact with water, organic solvents, mixtures of solvents, or vapors of solvents. Polymorphs and/or solvates of a drug molecule may have different chemical and/or physical properties. For example, polymorphs and/or solvates can differ substantially in melting point, chemical reactivity, particle size, shape, flow characteristics, caking, degree of hydration or salvation, optical and electrical properties, vapor pressure, and density. As a result, certain polymorphs of a drug molecule are more stable in a given environmental condition or selected solvent system than others.
A number of methods have been employed for characterizing polymorphs in pharmaceutical solids (H. Brittain. Methods for the Characterization of Polymorphs and Solvates, P
Polymorphism has a direct impact on the processability of drug substances and the quality of the final product. For example, physical properties including particle size, shape, flow characteristics, melting point, degree of hydration or solvation, and caking tendency can cause difficulties in chemical processing, material handling, compatibility with excipients, segregation in the blend, dissolution rate of a drug in aqueous media, and stability of the final dosage form. Whereas a change in chemical properties due to polymorph transformation can affect drug degradation induced by environmental factors such as heat, light, moisture, mechanical handling, oxygen, and interaction with excipients. The adverse effects may cause loss of production efficiency (time and cost), product quality and instability. Thus, it is desirable to utilize a proper polymorph in developing the dosage form.
The most stable polymorph of a drug substance is often used because it has the lowest potential for conversion from one polymorph to another, while a metastable polymorph may be used to enhance bioavailability. Gibbs free energy, thermodynamic activity, and solubility provide the definitive measures of relative polymorphic stability under defined conditions of temperature and pressure.
One polymorph may convert to another during manufacturing and storage, particularly when a metastable polymorph is used. Since an amorphous form is thermodynamically less stable than any crystalline form, inadvertent crystallization from an amorphous drug substance may occur. Because of the higher mobility and ability to interact with moisture, amorphous drug substances are also more likely to undergo solid-state reactions. Solid-state reactions include solid-state phase transformations, dehydration/desolvation processes, and chemical reactions.
In addition, phase conversions of some drug substances are possible when exposed to a range of manufacturing processes (H. G. Brittain and E. F. Fiese, Effect of Pharmaceutical Processing on Drug Polymorphs and Solvates, P
It is advantageous to have a method, which specifically can convert one polymorph or a mixture of polymorphs or a mixture of polymorphs and amorphous material to a desirable polymorph in the final dosage form during the formulation process. Benefits include simplifying the process steps, reducing manufacturing costs, and increasing processing ease for both the pharmaceutical active ingredient and the finished dosage form.
Zolpidem hemitartrate is known to exist in several polymorphs, among which are known the A, B, C, D, E, F, G, and H forms. See WO 01/80857 A1 by Teva Pharmaceutical Industries, Ltd. Teva Pharmaceutical Industries, Ltd. disclosed a method for converting Zolpidem polymorphs by solvating with water, methanol, ethanol, propanol, butanol, ethyl acetate, and the like. The results from the disclosed method often are irreproducible, particularly in production scale. In the disclosure, polymorph E was converted from other polymorphs isolated from water or solvent contact. The extra chemical processing steps and the need for solvent recovery steps required in the method can increase the production cost. Furthermore, some polymorphs are particularly difficult to process because of their physical properties.
Zolpidem hemitartrate may also undergo polymorph transformation under ambient storage conditions. We found Zolpidem polymorph E in the innovator's products according to the result of pXRD analysis; however, the starting material should be polymorph A according to the monograph of European Pharmacopoeia. It is desirable to have a consistent polymorph E in the finished product to provide the consistent release profile and bioavailability.
Among the various aspects of the present invention is a method for polymorph transformation of Zolpidem hemitartrate in a tablet matrix in the dosage formulation process. The conversion of polymorphs in a tablet during the dosage formulation process eliminates the need for a chemical process to produce a desirable form prior to formulating the active into the final dosage form.
Another aspect of the present invention is a method for polymorph transformation of Zolpidem hemitartrate in the process for coating substrates such as tablets or particles. In one embodiment, the transformation consists of converting polymorphs of Zolpidem hemitartrate to a stable polymorph in the spray-dried process.
Briefly, therefore, the invention is directed to a method for converting Zolpidem hemitartrate salt to a desired polymorph of Zolpidem hemitartrate salt comprising preparing a tablet comprising Zolpidem hemitartrate salt and solvating the tablet with an amount of a solvent to convert Zolpidem hemitartrate salt to the desired polymorph of Zolpidem hemitartrate salt.
The invention is further directed to a method for converting Zolpidem hemitartrate salt to a desired polymorph of Zolpidem hemitartrate salt comprising preparing a tablet comprising the hemitartrate salt of the compound and heating the tablet to convert the hemitartrate salt of the compound to the desired polymorph of the hemitartrate salt of the compound.
The invention is still further directed to a method for converting Zolpidem hemitartrate salt to a desired polymorph of Zolpidem hemitartrate salt comprising preparing a coating solution comprising Zolpidem hemitartrate salt and coating a tablet with the coating solution to convert Zolpidem hemitartrate salt to the desired polymorph of Zolpidem hemitartrate salt.
Other aspects of the invention are described in more detail below.
The present invention describes methods for transforming Zolpidem hemitartrate present in a variety of polymorphs into a desirable polymorph during the dosage formulation process to simplify the overall process, reduce production cost, and improve the product quality. In particular, the invention comprises a method for converting various polymorphs of Zolpidem hemitartrate or amorphous material to a desired polymorph in the tablet matrix. Note that the Zolpidem polymorphs discussed herein are those identified in WO 01/80857 A1 by Teva Pharmaceutical Industries, Ltd., the disclosure of which is hereby incorporated by reference in its entirety for all purposes.
In accordance with the invention, Zolpidem hemitartrate in any of its polymorphs or as a mixture of polymorphs or as an amorphous material is mixed with suitable pharmaceutical excipients to form a tablet comprising Zolpidem hemitartrate, which is then subjected to further treatment to convert the various polymorphs into a desired polymorph, such as, for example, polymorph C, polymorph D, or preferably into polymorph E. Typical pharmaceutical excipients include sugars such as lactose, fructose, maltodextrin, maltose, mannitol, sorbitol, sucrose, and mixtures thereof; organic acids including citric acid, tartaric acid, glycolic acid, and mixtures thereof; buffers including acetate, citrate, tartrate, oxalate, phosphate, carbonate, and mixtures thereof; polymeric materials including microcrystalline cellulose (MCC, Avicel®, available from FMC Corporation), hydroxymethylpropyl cellulose (HMPC, Opadry®, available from Colorcon), ethyl cellulose, propyl cellulose, starch, sodium starch glycolate, and mixtures thereof; and lubricants such as magnesium stearate. Preferably, the excipients are chosen to facilitate polymorph transformation. More preferably, the pharmaceutical excipients include lactose, magnesium stearate, and microcrystalline cellulose and/or sodium starch glycolate. The Zolpidem hemitartrate polymorphs and pharmaceutical carriers can be dry blended and compressed into tablets according to methods known in the art. A compressed tablets typically weighs about 120 mg and comprises between about 5 mg and about 10 mg Zolpidem hemitartrate.
Polymorphic transformations can be carried out by subjecting tablets comprising Zolpidem hemitartrate in any of its polymorphs to heat and/or environmental moisture under a controlled process condition. The tablets can be placed in an environmental chamber in which the temperature, relative humidity, and other conditions can be controlled. For example, the environmental chamber can be an oven which allows temperature and humidity control, and the tablets can be heated to temperatures in excess of about 40° C., preferably at least about 50° C., more preferably at least about 65° C. During heating, the relative humidity can be controlled such that the relative humidity is at least about 50%, preferably at least about 75%. Preferably, the humid atmosphere comprises water vapor. The Zolpidem hemitartrate polymorphs can be converted to desirable stable polymorphs according to these conditions within the tablet matrix. For example, it has been discovered that a heat treatment under relatively dry conditions can be used to convert Zolpidem hemitartrate polymorphs preferably to polymorph C. Under a heat and humidity treatment, the Zolpidem hemitartrate polymorphs preferably convert to polymorph D.
The Zolpidem hemitartrate polymorphs within the tablet matrix can be converted to polymorph E by high moisture or wetting treatment with controlled drying. The wetting treatment can occur by spraying or immersion with the condition that the treatment achieves sufficient wetting throughout the entire tablet without compromising tablet integrity. To achieve sufficient wetting, process conditions such as water flow rate, air flow, and drying temperature are balanced and optimized depending upon the size of the pan coater or other equipment, the batch size, the tablet shape, and tablet hardness. Although precise values for water flow rate, air flow, and drying temperature vary as a function of the above named parameters, it is important that they be balanced to sufficiently wet the tablets to allow moisture to disperse throughout the tablet with simultaneous drying. Preferably, the tablets are wetted with water. In an exemplary wetting process, the tablets are charged to a pan coater, rotated, and wetted by spraying with water under conditions of moderate heating and air flow rate. The tablets are preferably coated with HMPC, marketed as Opadry®, to harden the tablets and also increase the tablets' hygroscopicity. Preferably, process conditions are optimized to allow the tablets to absorb at least about 5% by wt. water for sufficient wetting to convert the Zolpidem hemitartrate polymorphs to polymorph E without compromising the integrity of the tablet. It has been discovered that wetting at a temperature between about 25° C. and about 45° C. with an inlet air flow of about 22 CFM and a pan speed of about 10 rpm is sufficient to allow the tablets to absorb about 5% by wt. water.
It has also been discovered that wetted tablets comprising polymorph E, preferably prepared according to the above-described method, can be heat treated to a temperature of at least about 50° C., more preferably at least about 80° C. to convert the polymorph E to a different polymorph, for example, polymorph C.
Alternatively, polymorphic transformations can be carried out by spraying placebo tablets with a solution or dispersion comprising Zolpidem hemitartrate in any of its polymorphs or as a mixture of polymorphs or as an amorphous material during a coating process. As a result of the slurry preparation and coating process, the Zolpidem hemitartrate polymorphs are substantially converted to polymorph E in the coated tablet.
To prepare the coating solution, Zolpidem hemitartrate is dissolved or suspended in water, aqueous solution, or a mixture of water and a minor amount of pharmaceutically acceptable solvent such as methanol, ethanol, propanol, butanol, or ethyl acetate. Preferably, the solvent is water. The aqueous solution comprising Zolpidem hemitartrate may also comprise polymeric binders, such as Opadry®.
Substrates useful for coating with the Zolpidem hemitartrate solution are preferably pills or tablets comprising pharmaceutical excipients commonly used in making tablets or particles for solid dosage forms. Such excipients include those listed above. Preferably, the placebo tablet comprises lactose, microcrystalline cellulose, and magnesium stearate. Another preferred placebo tablet formulation comprises lactose, microcrystalline cellulose, magnesium stearate, hydroxymethylpropylcellulose, and sodium starch glycoate. Preferably, the substrates suitable for coating exhibit sufficient integrity and water-absorbing capacity when water, aqueous solution, or a mixture of solvents is applied to it.
The aqueous solution of Zolpidem hemitartrate, or the suspension of Zolpidem hemitartrate in a suitable solvent system, can be applied to the substrates using conventional spray coating equipment such as a pan coater or a fluid bed coater. It has been discovered that spray coating placebo tablets with a solution comprising Zolpidem hemitartrate yields active tablets comprising Zolpidem hemitartrate polymorph E.
The following examples further illustrate the practice of the present invention.
Zolpidem hemitartrate (Polymorph A), lactose, and magnesium stearate were thoroughly mixed in a beaker. The amount of each component is shown in Table 1. The powder blend was fed into a tablet press (Korsch PHI 06) and compacted to make tablets using 0.3437 inch deep cup round toolings. Each tablet weighed about 120 mg, and had a hardness value about 10 kPa.
A sample of the tablets of Example 1 was heated in an oven at 65° C. for 18 hours. Another tablet sample was heated in a humidity-controlled oven (75% Relative Humidity, 50° C., 24 hours). The above treated samples, as well as untreated powder blend and untreated tablets from Example 1, were analyzed by powder x-ray diffraction (pXRD).
Results from pXRD analysis indicated that the Zolpidem hemitartrate in the untreated powder blend and untreated tablets remained as polymorph A. The Zolpidem hemitartrate in the tablets treated at 65° C. transitioned into polymorph C. The Zolpidem hemitartrate in the tablets treated with heat and humidity transitioned into polymorph D. The results are shown in Table 2.
Tablets containing Zolpidem hemitartrate polymorph A (Example 1) were treated to convert the Zolpidem hemitartrate polymorph A to stable polymorph E according to the following protocol:
Under a slow spray condition, when the tablets absorbed only 1% by wt. water, there was no detectable polymorph change in the tablets after 24 hours. The water spray procedure was repeated again and the tablet water content was increased to about 5% by weight. The tablet sample was analyzed by pXRD, and the Zolpidem hemitartrate was found to have converted into polymorph E. See Table 3d.
Tablets from Example 3 were heated in an oven at 80° C. overnight and analyzed by pXRD. Zolpidem hemitartrate polymorph E in the tablets converted to polymorph C.
Placebo tablets were prepared having components shown in Table 4a. The tablets were prepared according to the following protocol:
The tablets resulting from Step 5 were shown by pXRD to contain Zolpidem hemitartrate polymorph E.
To test the stability of the Zolpidem hemitartrate polymorph E in the coated tablets of Example 5, the tablets were subjected to the following post-treatment steps
The tablets were analyzed by pXRD, which showed that the Zolpidem hemitartrate remained in polymorph E.
Zolpidem hemitartrate having a mixture of several polymorphs (A, C, and D) was used to coat a placebo tablet (preparation described in Example 5) according to the following steps:
The Zolpidem hemitartrate in the resulting coated tablet was found, by pXRD analysis, to be polymorph E.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
As various changes could be made in the above without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US06/37586 | 9/28/2006 | WO | 00 | 4/11/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60727371 | Oct 2005 | US |
