DD289468B5 - MEDICAMENTAL TECHNOLOGY FOR PREPARING AN ALPRAZOLAM DRUG MODEL - Google Patents

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Pharmaceutical Technological Process for Preparing an Alprazolam Drug Form

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

The achievement of a good content uniformity in very low-dose dosage forms with less than one percent active ingredient content is known to be fraught with difficulties. The particle size, particle morphology and the production process play a crucial role here.

Thus, US Patent 4721-709-A describes the preparation of fine particles of poorly soluble benzodiazepines (including alprazolam) containing solid dosage forms having good dissolution and absorption properties. The required fine crystallite size is achieved by Precipitation of the active ingredient from an organic solvent (acetone, methanol, ethanol) in the presence of a fine-grained excipient by the addition of water.

In US Patent 4508-726-A, micronization is proposed in part and, in the case of salts of alprazolam, also precipitation from an organic solvent.

From DE-OS 3332830 the production of alprazolam tablets is known, wherein alprazolam is mixed with dicalcium phosphate and granulated with a 7.5% aqueous methylcellulose solution. However, nothing is said about a crystal form.

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

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

The invention was based on the object of developing a technically simple and economical process without dilution 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 accordance with the invention in that alprazolam is suspended in water, preferably in at least 3, especially 10 to 30 parts by weight of water and under polarization microscopic and X-ray diffractomotive control of the hydration process is controlled so that the active ingredient completely in very fine crystalline platelet-shaped and in water well dispersible dihydrate is converted and distributed homogeneously by spraying on solid galenic excipients. The needle-shaped α-modification is advantageously used, which forms fine-crystalline pseudomorphs of the dihydrate after the α-modification in the reaction with water, which completely decompose into the single crystallites under appropriate conditions. To control the crystallite size and distribution, polarization microscopy is advantageously used. To control dihydrate formation, X-ray powder diffractometry is preferably used.

After the hydration process, a viscosity-increasing additive such as gelatin, sodium carboxymethyl, methyl, hydroxyethyl cellulose, tragacanth, pectin, sodium alginate, dextran is added to the dihydrate suspension. This suspension is sprayed onto a mixture of solid galenic carriers such as lactose, 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 2 to 3 ° rather melting ß-modification, however, 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)

α-alprazolam + H2O β-alprazolam + H ₂ O

Alprazolam dihydrate and alprazolam dihydrate

X-ray diffractometry controllable. The dihydrot is very stable. The dehydration begins only above 60 to 70 ⁰ C, with the maximum of the DTG curve (1. Derivation of the thermogravimetric curve) is about 90 ° C.

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

No. α-modification Int. (%) ß-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 O. = 31 '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 26 44 29 38 0.445 45 0.441 23 0.441 25 46 0.436 0,432 17 17 47 0.424 12 0.423 48 3 0.419 49 0.416 6 4 6 50 0.410 0.410 0.412 13 51 0,407 23 52 14 0.402 35 53 0.394 0.393 34 54 18 0.391 55 0.388

Continuation Tab. 1

No. α-modification Int. {%) ß-Moclifikation Int. (%) dihydrate Int. (%) d {nm) 20 d (nm) d (nm) 56 0.385 13 4 100 57 0,382 81 0,380 0,382 14 58 0.370 22 75 0.370 14 59 0.364 24 0,366 0,366 60 0,360 22 61 38 0.358 9 62 0.354 20 0.354 63 0.352 32 64 20 21 0.349 65 0,34E 11 0.344 19 66 0.340 19 0.342 25 67 0.338 40 0,339 11 68 12 0,336 27 0,336 69 0.333 18 0.332 21 10 70 0.326 21 0.328 0.327 25 71 0,322 19 0.321 72 31 0.319 11 73 0.316 21 0.315 74 0,314 26 13 19 75 0.311 19 0.312 0.311 14 76 0.309 11 29 0.309 15 77 0.306 10 0.306 0.307 8th 78 0.304 0.304

d = lattice plane distance Int = relative intensity

However, the inventive solution set out above was by no means obvious for the reasons given below. Even one and the same compound can form different crystal structures with different habit of the respective crystals (polymorphic). For example, α-alprazolam forms needles and β-alprazolam panels. However, the crystal habit is not determined solely by the crystal structure, but depends essentially on the crystallization conditions (type of solvent or solvent mixture, concentration-temperature-time regime, mechanical influence by stirring, presence of traces of other substances), the achievement a particular crystal habit in mass crystallization is one of the most difficult technical tasks. For example, 3,7-dimethyM- (5-oxohexyl) purine-2,6-dione (pentoxyfylline), with the same crystal structure, forms needles or thick sheets, depending on the conditions of crystallization, depending on conditions of very different size and shape (length to thickness). , For a-alprazolam, differences in needle dimensions of more than 1:10 were found, depending on the crystallization conditions. The claimed uniform crystallite size of the alprazolam dihydrate can only be achieved in situ conversions of preexisting needles under the conditions given, and is by no means typical for hydrate formation par excellence. Platelet-shaped crystals also form on hydration from the β-alprazolam panels, but the rearrangement is significantly slower and does not result in the desired uniform crystal size. The primary crystallization of alprazolam dihydrate from aqueous medium produces thick sheets of various sizes.

Since anhydrous alprazolam is not hygroscopic and the solubility in water at room temperature is only 0.009%, it was completely surprising even to those skilled in the art that when suspended in water in a short time hydrate formation occurs quantitatively with crystal conversion.

It was also not foreseeable by those skilled in the art that under the specified conditions, a platelet-shaped hydrate of strikingly uniform texture and a uniform particle size <15pm is formed, which for the achievement of a good content uniformity according to Johnson, Pharm. Acta HeIv. 47.546 is required. In the o. G. low water solubility is the achievable by the claimed method without further technical aids particle size a prerequisite for good bioavailability.

On the other hand, in the hydration of preexisting, nearly isometric carbamazepine crystals, needles of varying sizes grow rapidly to almost macroscopic dimensions.

The successful solution of the problem was not obvious even with knowledge of DE-PS 1955349, as the alprazolam structurally similar, also sparingly soluble in water substances such. For example, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-1,2,4-triazole (4,3) - (2,4) benzodiazepine (triazolam) and 7-chloro 1-methyl-5-phenyl-1H-1,4-benzodiazepine-2 (3H) one (diazepam) does not form hydrates by simply suspending in water.

embodiments

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 2ma .-% 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 tablet 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 ma .-% Gola'.inelösu ig. The suspension is sprayed onto 181.5 g of microcrystalline cellulose in the fluidized bed. After drying, your granules are mixed with 1 g of magnesium stearate 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 0.25mg of alprazolam.

Result of testing for uniform drug content:

0,2452mg; s = 0.0064

Example 4

67.0 g of alprazolam of the α-modification are suspended in 0.51 of water. The suspension is homogenized in a corundum disk mill. The mixture is then stirred for 2 hours and combined with 1.5110 ma .-% gelatin solution. The suspension is sprayed onto a mixture of 10.0 kg of lactose, 4.3 kg of potato starch and 134 g of 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 pressed into tablets having a mass of 110 mg. Each tablet contains 0.5 mg of Alprazolam.

Comparative data on bioavailability

The bioequivalence was investigated on 11 healthy volunteers after a single oral administration of the tablets according to the invention according to Example 4 with a dosage of 1 mg (= 2 tablets of 0.5 mg) against an internationally recognized top preparation.

Result:

• ml " ') Embodiment 4 international top preparation Ux (h) 1.41 + 0.9 1.41 ± 1.06 c _m .x (ng 17.0 ± 4.0 18.8 + 6.2

AUCfnghmr '114.9 ± 25.8

119.9 ± 28.0

The above-mentioned data relevant for the assessment of bioequivalence do not differ significantly. This proves that the same effect is achieved with the simple method according to the invention.

Comparative data for in vitro drug discovery

The drug release from tablets according to Embodiment 3 and 4 was in e ^! Paddle Apoaratur according to DAB10 in buffer pH 6.8 compared to a internntionalen top preparation tested. The content was determined by UV spectrophotometry after separation by HPLC.

Result:

released Alprazolam

Time (min) Embodiment 3 International

tip preparation

20 30 96.5 96.5 1.66 1.66 95.3 4.09 97.2 4.94 4,84 2,63 102.3 0.78 102.9 1.07 Result: Time (min) approved alprazolam Embodiment 4 top international preparation (%) S, ei (%) (%) S _fe i (%) 20 30 98.2 98.8

The results show that the tablets produced according to the invention have a comparable in vitro drug release as the international syringe preparation.

Comparative data on salary index

The content uniformity of 10 tablets each was tested on several tablet lots prepared according to Embodiment 3 and 4, respectively. For the 10 individual values the absolute and relative standard deviation was calculated. The standard deviation of the analytical method was used to calculate the standard deviation of the analytical method.

Result:

Embodiment 3

abolute standard deviation of the manufacturing method mean value of η = 5 batches: 0.0050mg relative standard deviation of the manufacturing process: 2.00%

Embodiment 4

absolute standard deviation of the manufacturing process mean of η = 5 batches: 0.0082mg relative standard deviation of the manufacturing process: 1.64%

international top preparation

Relative standard deviation of the production method: 2.81% The low standard deviations prove that with dom manufacturing method according to the invention a good content uniformity, comparable to a top international preparation is achieved.

Data on stability

to record the stability of tablets was prepared according to Embodiment 3 or 4, the drug release checked.

Result:

released Alprazolam after 30 min

shelf life Embodiment 3 s,., (%) Embodiment 4 S ₁₈₁ (%) in months (%) 1.45 (%) 0.87 0 103.6 0.97 103.6 0.80 6 102.6 1.39 99.8 1.92 12 100.4 1:47 103.9 0.60 18 101.7 1.76 100.1 1.67 24 102.5 101.5

The results demonstrate that in the period under study, when stored under normal conditions, drug release has no change.

Claims (5)

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, water is suspended. 3. The method according to claim 1 and 2, characterized in that the Dihydratsuspension gelatin or Natriumcarboxymethylcelluiose be added. 4. Process according to claims 1 to 3, characterized in that are used as solid galenic excipients lactose, starch, starch derivatives, cellulose powder, microcrystalline cellulose or cellulose derivatives. 5. Process according to claims 1 to 4, characterized in that the granules further additives are added and this is then pressed into tablets or filled into hard gelatin capsules.