Processing

Please wait...

Settings

Settings

Goto Application

1. WO2011001214 - SURFACE AMORPHIZATION OF PHENPROBAMATE

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

Description

Title of Invention: SURFACE AMORPHIZATION OF PHEN- PROBAMATE

[1] This invention is related to a pharmaceutical compositions of phenprobamate having eligible flowability and eligible tabletting properties.

[2] Phenprobamate is firstly delineated in the patent GB 837718. It is a centrally acting skeletalmuscle relaxant, with additional sedative and anticonvulsant effects. However it leads to many problems in tabletting and granulation due to poor flowability. The poor flowability is arising from structure of phenprobamate which is crystalline shape (Figure 1- obtained by Malvern Morphologi G3 Particle Characterization Image Analyzer ) .

[3] The effect of crystal habit on tablet properties was explained by Shell (1963- X-ray and crystallographic applications in pharmaceutical systems. Ill: Crystal habit quantitation. J. Pharm. Sci. 52, 100-101). He described crystal habits by measurement of preferred particle orientation that is related to the compression characteristics of the powder.

[4] The tableting behavior, flowability and the tendency to stick to the punches of drugs can be affected by changes in the crystal habit. By changing the crystal shape, the compression and tableting behavior can be affected. Therefore it is important to find a crystal shape that is suitable for tabletting. However , generally, the solution of changing of crystal habit takes long times. Therefore industry needs a practical solution to eliminate of flowability problem of phenprobamate.

[5] When using related techniques of pharmaceutical technology , phenprobamate causes substantial difficulties due to physical properties in the preparation of solid oral forms as direct compression with dry granulation. The melting point of phenprobamate is very low 1010C -1040C which makes tabletting techniques almost impossible during compression a heat effect is developed which has an impact on phenprobamate crystal habit.Thusthe conventional directtabletting process has thedis advantages that the powder mixture to be compressed flows poorly, the dosing accuracyis inadequate, the tabletting speed is not sufficiently rapid and capping of these tablets cannot be avoided, which in turn makes coating difficult.

[6] Another serious problem is to obtain surface amorphization since crystalline surface of phenprobamate does not permit a suitable acive ingredient for tabletting. Crystalline structure is determined by XRD (Figure X). Due to low melting point of phenprobamate, dry granulation technics lead to capping. By applying methods according to this invention, the crystals of phenprobamate become soften and more regular in

shape leading an improved compressibility and flowabilityand leading no tendency to stick to the punches as well as no capping tendency.

[7] The technical problems mentioned above is solved by using of wet granulation or coating with a binder or mixtures of binders. Accordingly, a binder or mixtures of binders are dissolved or suspended in water or solvent or mixtures thereof.

[8] According to this invention ;

[9] - Phenprobamate is coated with binder mixture or,

[10] - Mixtures of phenprobamate and an excipient or excipients are coatedwith binder mixture or,

[11] - Phenprobamate is granulated with binder or binders in which granulation is wet granulation or

[12] - Mixture of phenprobamate and an excipient or mixtures of phenprobamate and excipients are granulated in which granulation is wet granulation.

[13] Phenprobamate may be in combination with an active pharmaceutical ingredient or ingredients. Accordingly;

[14] - Phenprobamate alone is coated with binder mixtureor,

[15] - Mixtures of phenprobamate and an active pharmaceutical ingredient or ingredients are coated with binder mixture or,

[16] - Mixtures of phenprobamate and an active pharmaceutical ingredient or ingredients and an excipient or excipients are coated with binder mixture or,

[17] - Phenprobamate is granulated with binder or binders in which granulation is wet granulation or

[18] - Mixtures of phenprobamate and an active pharmaceutical ingredient or ingredients are granulated with binder or binders in which granulation is wet granulation or,

[19] - Mixture of phenprobamate and an active pharmaceutical ingredient or ingredients and an excipient or excipients are granulated in which granulation is wet granulation.

[20] Whereby the binder mixture consists of a solution or a suspension of a solvent or a solvent mixtures with a binder or mixture of binders and if needed other necessary excipient or excipients. Optionally, binder solution or suspension may contain an excipient or excipients along with binder or binders.

[21] The binder, which is used in binder mixture, may be, but not limited to, starch, polyethyleneglycol, microcrystalline cellulose, hydroxypropyl cellulose, hydrox- ypropylmethyl cellulose,carboxymethylcellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof. Preferred binder is povidone .

[22] Binder mixture as solution or suspension may be in water, organic solvent or any suitable pharmaceutical ingredient.

[23] Organic solvents, used in preparation of solution may be ,but not limited to, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, 2-methyl-l-propanol etc. ; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc. ; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate etc. ; hydrocarbons such as heptane ; halogenated hydrocarbons such as dichloromethane.

[24] Organic solvents can be used alone or in combination with water. Mixtures of

organic solvents may also be used. Using of mixtures of organic solvents can be in an appropriate ratio.

[25] Solution or suspension agent may contain organic or inorganic acid.

[26] Preferable examples of organic acids are formic acid, acetic acid, fumaric acid,

tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, p- toluenesulfonic acid .

[27] Preferable examples of inorganic acid is hydrochloric acid which is in the form of solution in water.

[28] Solution or suspension agents are not accepted as numerus clausus may be selected any other suitable agents or mixtures thereof.

[29] According to this invention pharmaceutical composition may be in the form of such as tablet, bilayer or trilayer tablet etc.

[30] Where phenprobamate is used in combination with an active pharmaceutcal ingredient or ingredients , phenprobamate and an active pharmaceutcal ingredient or ingredients may be granulated alone or may be co-granulated with an active pharmaceutical ingredient or ingredients and whatsoever. Where granulation is fulfilled alone for each active pharmaceutical ingredient, each active pharmaceutical ingredient is dispersed within its own pharmaceutically acceptable carrier.

[31] Example 1

[32] This example is related to phenprobamate and paracetamol combination. The tiers of manufacturing ;

[33] 1. Sieved phenprobamate is added to microcyrstalline cellulose and croscarmellose sodium then the mass is mixed .

[34] 2. Polyvinylpyrrolidone is dissolved in deionized water ,

[35] 3. Polyvinylpyrrolidone solution is sprayed onto the mixture prepared (in step 1) in order to form a granular mass in fluid bed granulator,

[36] 4.At the end of drying process, the mixture is sieved .

[37] 5. Colloidal silicon dioxide is sieved. Then colloidal silicon dioxide is mixed with a small quantity of the granulate.

[38] β.Paracetamol DC is added to the granulate and colloidalsilicon dioxide is added to the dried and sieved granulate. The mixture is blended with the granulate.

[39] 7. Magnesium Stearate is sieved then added to the mixture.The final mixture is

mixed.

[40] 8. Final mixture is tabletted.