DD289468A5 - MEDICAMENTAL TECHNOLOGY FOR PREPARING AN ALPRAZOLAM DRUG MODEL - Google Patents

Abstract

The invention relates to a medicament technology process for the preparation of an alprazolam dosage form. The pharmaceutical technology process for preparing a solid dosage form containing alprazolam with good bioavailability and very good unit uniformity is characterized in that crystalline alprazolam, advantageously the alpha modification, is converted into very finely crystalline dihydrate by a controlled hydration process and this suspension is sprayed onto a mixture of solid galenic carriers such as lactose, starch, starch derivatives, cellulose powder, microcrystalline cellulose and / or cellulose derivatives are homogeneously distributed. {Alprazolam modification; Alprazolam dihydrate; hydration; Pharmaceutical Technological Process; bioavailability; Content uniformity; galenic carriers}

Description

Field of application of the invention

The invention relates to a pharmaceutical technology process for the preparation of an alprazolam-containing, per os-administrable drug form of good bioavailability and very good content uniformity. The pharmaceutical technology process can find application in the pharmaceutical industry.

Characteristic of the known state of the art Achieving a good content uniformity in very low dosage forms with less than one percent Active substance content is known to be fraught with difficulties. The particle size, particle morphology and the Manufacturing processes play a crucial role here. Thus, US Patent 4721-709-A discloses the production of fine particles of poorly soluble benzodiazepines (including alprazolam).

containing solid dosage forms with good dissolution and absorption properties besenrieben. The required fine

Crystallite size is determined by precipitation of the active ingredient from an organic solvent (acetone, methanol, ethanol) Presence of a fine-grained excipient achieved by adding water. In US Patent 4508-726-A micronization is proposed in part and in salts of alprazolam also the Precipitation from an organic solvent. From DE-OS 3,332,830 the preparation of alprazolam tablets is known, wherein alprazolam with dicalcium phosphate

mixed and granulated with a 7.5% aqueous methylcellulose solution. However, nothing is said about one

Testified crystal form. Object of the invention

The aim of the invention is the industrially simple preparation of a dosage form containing alprazolam per os with good bioavailability and very good content uniformity.

The disadvantages to be avoided by additional process steps, such as micronization or precipitation from an organic solvent.

Explanation of the essence of the invention

The invention had the object of developing a technically simple and economical process without the use of organic solvents and without micronization for the preparation of per os administrable alprazolam-containing drug forms with good bioavailability, very good content uniformity and sufficient stability of the drug form. The object is achieved in the Wei se, that alprazolam in water, preferably suspended in at least 3, especially 10 to 30 parts by weight of water and under polarization microscopic and X-ray diffractometric control of the hydration process is controlled so that the active ingredient completely in very finely crystalline platelet-shaped and in water readily dispersible dihydrate is converted and homogeneously distributed by spraying on solid galenic excipients. The needle-shaped α-modification is advantageously used, which in the reaction with water finely crystalline pseudomorphoses of

Dihydrate forms after the α-modification, which completely decompose under appropriate conditions in the Elnzelkristallite. To control the crystallite size and the distribution, polarization microscopy is advantageously used. To control dihydrate formation, X-ray powder diffractometry is preferably used. After the hydration process, the dihydrate suspension is advantageously supplemented with a viscosity-increasing additive, such as gelatin, sodium carboxymethyl, methyl, hydroxyethylcellulose, tragacanth, pectin, sodium alginate, dextran. This suspension is sprayed onto a mixture of solid organic carriers, such as Latkose, starch, starch derivatives, cellulose, cellulose derivatives, silica. The dry granules further adjuvants can be added in a known manner. The granules can be compressed into tablets or filled into hard gelatin capsule. Alprazolam crystallizes in two different crystalline modifications with different crystal habit. The more stable α-modification (melting range 228-231 ⁰ C) forms long needles, the 2 to 3 grd rather melting ß-modification in contrast tabular crystals. Upon contact with water, both modifications are converted to the tabular crystal dihydrate. These three crystalline phases can be clearly identified according to the different X-ray diffraction diagrams (Table 1).

 So are the crystal reactions (hydration processes)

a-alprazolam + H ₂ O alprazolam dihydrate as well

β-alprazolam + HjO alprazolam dihydrate

X-ray diffractometry controllable. The dihydrate is very stable. The dehydration begins only above CO to 70 ° C, the maximum of the DTG curve (1st derivative of the thermogravimetric curve) is about 9O ⁰ C.

Tab. 1: X-ray diffraction patterns (powder diffractograms) of crystalline alprazolam phases

No. α-modification Int. (%) p-modification Int.% dihydrate Int. (%) d (nm) d (nm) d (nm) 6 1 1.54 13 2 26 1.48 3 1.44 5 4 9 1.36 5 1.31 15 6 1.25 14 7 1.18 2 8th 1.10 29 9 1.05 18 10 2 91 0.95 11 0.92 0.92 3 12 0.88 11 13 6 0.84 14 0.787 72 15 7 0.782 16 0.747 23 17 17 61 0.737 18 0.721 9 0.725 19 0.706 37 18 17 20 0.685 22 0,690 0.659 6 21 0.677 51 0,680 22 0.671 33 25 23 0.652 6 0,654 24 0.628 10 34 25 0.622 7 0.623 26 0.608 15 27 17 54 0.597 28 0.591 31 0.592 3 29 0.579 0.579 5 30 41 3 0.569 3 31 0.560 45 0.556 0.560 32 0.531 20 33 19 0.572 34 0.522 19 35 0.502 11 36 0,500 21 37 67 42 0.492 38 0.481 0,483 37 39 0.479. 9 40 39 87 0.474 41 0.461 40 0.461 42 0.458 20 20 43 0,450 0.452

No. α-modification Int. (%) ß-modification • 0,380 • Int. % dihydrate Int. (%) 32 d (nm) d (nm) d (nm) 26 44 29 0,366 38 0.445 19 45 0.441 23 0.441 25 25 46 0.436 0,432 0.358 17 17 11 47 0.424 12 0.423 48 3 0.419 10 49 0.416 6 4 6 25 50 0.410 0.410 0.344 0.412 13 51 0,407 23 52 14 0.402 35 53 0.394 0,336 0.393 34 19 54 18 0.332 0.391 14 55 0.388 20 0.328 15 56 0.385 13 4 100 8th 57 0,382 81 0.319 0,382 14 58 0.370 22 0.315 75 0.370 14 59 0.364 24 0,366 60 0,360 0.312 22 61 38 9 62 0.354 20 0.306 0.354 63 0.352 64 20 21 0.349 65 0.345 11 66 0.340 19 0.342 67 0.338 40 0,339 68 12 27 0,336 69 0.333 18 21 70 0.326 21 0.327 71 0,322 19 0.321 72 31 11 73 0.316 21 74 0,314 26 13 75 0.311 19 0.311 76 0.309 11 29 0.309 77 0.306 10 0.307 78 0.304 0.304

Interplanar spacing relative intensity

embodiment

example 1

1.25 g of alprazolam of the α-modification are suspended in 25 ml of water and homogenized using a corundum disk mill (grain size 80). The suspension is stirred for 2 hours and then combined with 150 g of a 2 wt .-% sodium carboxymethylcellulose solution. The suspension is sprayed onto 195.75 g of microcrystalline cellulose in the fluidized bed.

After drying, 1 g of magnesium stearate is added to the granules and the granules are pressed into tablets. Each tray contains 0.5 mg of Alprazolam.

Example 2

0.5 g of alprazolam of the α-modification are suspended in 10 ml of water and homogenized using a corundum disc mill (grain size 80). The suspension is stirred for 2 hours and then combined with 180 g of a 10% by weight gelatin solution. The suspension is sprayed onto 181.5 g of microcrystalline cellulose in the fluidized bed. After drying, 1 g of magnesium stearate is added to the granules and the granules are filled into capsules of size 1 with a filling weight of 200 mg. Each tablet contains 0.5 mg of Alprazolam.

Example 3

33.5 g of alprayl α-modification are suspended in 0.5 l of water. The suspension is homogenized with a corundum disk mill (grain size 80). Thereafter, it is stirred for 2 hours and combined with 1.5110Ma .-% gelatin solution. The suspension is sprayed onto a mixture of 10.2 kg lactose, 4.3 kg potato starch and 66 g calcium lactate in the fluidized bed. It is then granulated with another 1.7110Ma .-% gelatin solution. After drying, 71.5 g of magnesium stearate are added to the granules and the granules are compressed into tablets having a mass of 110 mg. Each tablet contains 0.25 mg alprazolam.

Result of testing for uniform drug content:

0.2452 mg; s = 0.0064

Claims (6)

1. A pharmaceutical technology process for preparing an alprazolam-containing dosage form which can be administered per os, which comprises converting alprazolam by hydration into finely crystalline dihydrate, adding a viscosity-increasing substance to the dihydrate suspension and applying the suspension to solid galenical carriers. 2. The method according to claim 1, characterized in that crystalline alprazolam of α- or ß-modification in at least 3 parts by weight, preferably 10 to 30 parts by weight of water is suspended. 3. The method according to claim 1 and 2, characterized in that the aqueous suspension is stirred until the α- or ß-modification is completely converted into the platelet-shaped, crystalline dihydrate. 4. The method according to claim 1 to 3, characterized in that the dihydrate suspension viscosity-increasing substances, preferably gelatin or sodium carboxymethyl cellulose are added. 5. The method according to claim 1 to 4, characterized in that the suspension is sprayed onto solid galenic carriers such as lactose, starch, starch derivatives, cellulose powder, microcrystalline cellulose or cellulose derivatives. 6. The method according to claim 1 to 5, characterized in that the granules further additives are added and this is then pressed into tablets or filled into hard gelatin capsules.