US2857681A - Process for drying organic pharmaceuticals - Google Patents

Description

United States Patent PROCESS FOR DRYING ORGANIC PHARMACEUTICALS Sidney Beinfest, Berkeley Heights, Joseph Halpern, New Providence, Sidney Gister, Bound Brook, and Phillip Adams and Michael Zelkind, Berkeley Heights, N. J., assrgnors to Berkeley Chemical Corporation, Berkeley Heights, N. J., a corporation of New Jersey Application November 20, 1957, Serial No. 697,529

6 Claims. (Cl. 34-15) This invention relates to new and useful improvements in the obtaining of pharmaceuticals of high bulk density. More particularly it relates to a process of the nature indicated wherein these pharmaceuticals, after initial processing, are treated as a high concentration of solids in a heterogeneous system with a volatile liquid and at a controlled temperature above the melting point of the pharmaceuticals to ultimately provide the improved products.

Many normally solid organic pharmaceuticals in order a to obtain the requisite purity after preparation are con-: ventionally crystallized from volatile liquids, separated from most of the mother liquid by mechanical means, such as filtration or centrifugation, and then dried.

Their drying is done by standard'means, e. g. using rotary kiln, atmospheric shelf, and vacuum shelf dryers. All these methods result in products of rather low bulk density, e. g., for 2-methyl-2-n-propyl propane 1,3 dioldicarbamate, a well known tranquilizer, 0.30 to 0.37

gms./cc. This in turn results in low fiowability andconsequent clumping in containers and hoppers. In addition as many of the crystals are electrostatic,.dusting is a problem. These difficulties are particularly undesirable in pharmaceuticals because of difficulty in'handling and potential hazards from exposure of pharmacologically active dusts.

These physical characteristics further lead to problems.

in tabletting of the powders because of poor compressibility. Excessively large tablets are required for. stand-- Because of these factors wet granulation has been necessarywith' ard: dosages and concomitant large packages.

consequent regrinding to improve fiowability. These expedients are costly and tablet size is still larger than ob-' tained by the process of this invention.

This invention provides an improved method of overcoming all these beforementioned difficulties. The method comprises crystallizing the pharmaceutical from a volatile liquid, separating and removing amajor proportion of. .the liquid from the pharmaceutical-liquid system, to leave a high concentration of solid pharmaceutical product in a heterogeneous system with theresidual volatile liquid, stripping oil the remaining volatile liquid from the pharmaceutical, conveniently at a subatmospheric pressure, and at a temperature above the melting point of the pharmaceutical at the pressure utilized, but below its decomposition temperature, under which conditions the pharmaceutical is liquid, then cooling the pharmaceutical to solidify it and finally comminuting it to obtain the high bulk density product. Further details follow.

It is surprising to learn that in this manner the bulk density can be improved as much as 100%, e. g., for 2- methyl-Z-n-propyl-propane, 1,3 diol dicarbamate from 0.35 to 0.7 gms./cc. after grinding. The fiowability is increased and the need for wet granulation avoided. The dried material can be tabletted directly or granulations can be prepared by dry slugging. All these advantages are obtained with a reduction in drying time requirements. The tablets produced have a volume de- 2 crease of or more for the same dosage as compared... to tablets prepared from conventionally dried material.

The organic pharmaceuticals towhich this inventionis. applicable, arethose thatare normally solid (at conven-I tional atmospheric conditions), I have a decomposition. temperature at least 10 C. above their melting points,. and arecapable of being purified by crystallization from a volatile liquid. I l v C This invention is thusapplicable to pharmaceuticals" of a wide variety of chemical structures, e. g., esters,'j amides, ethers, diols and polyols, acids, phenols, keiton'es pyrimidines, etc. This invention is particularly suitable to the class of materials selected from the group consisting of .alkanediols and .alkanediol dicarbamates. Examplesof specificcompounds towhich this invention areapplicable include. butane, 1,3 diol dicarbamate, 2-meth yl-2-nepropyl-propa'ne' 1,3 diol dicarbamate, beta ;glu q cosepentacetate, carbromal, barbital, acetyl carbromal, thymol, lauric acid, diethyl' stilboestrol, and mephenesina The volatile-liquids from-which the organic pharmaceue ticals are crystallized or recrystallized are water or typi cal-organicisolvents and mixtures of the two. The or naphtha, acetone, acetic acid, etc.

The actual crystallization procedure 1 is, nopart of 1 invention and need notgbe elaboratedupon here. 7 4 The major proportionof the volatile liquid is then removed from the solid pharmaceutical-volatile liquid s ystern by mechanical separation such as centrifuging or filtration. f H

The removal of the major proportion of, the volatile liquid leaves a high concentration of solid pharmaceuticah in a heterogeneous system with the residual volatile liq-f uid. The term filter cake? is also utilized to connote this type system which normally has a liquid content of about, 10 to 70 wt. percent, r H The remaining volatileliquid is 'then stripped'ofi from the pharmaceutical at a temperature above the melting point of the pharmaceutical at the'pressure utilized, but" below its decomposition temperature. The pressures can range-from sub to superatmospheric depending upon the solvent and temperature required. The pharmaceutical is thus liquid under these conditions. It is to be,under -j{ :stood, of course, that the highly concentrated hetero-g;

geneous system can be heated to the desired controlled" temperature prior to the application of the -pressure which is then utilized in the stripping operation. -The; temperatures given below refer to the terminal tempera tures since in heating up the system it will of course have to go through the lower temperatures first Finally the I pressureutilized iseasily'chosen so as to permit the ob-x taining of the desired temperature during-the stripping operation which will permitmelting but not decomposi-;= tion. The exact temperature figures vary from each compound, e. g. butane 1,3 diol dicarbamate, the temperature utilized is in the range of about 152l70 C. and for 2-methyl-2-n-propyl-propane 1,3 diol dicarbamate, it is in the range of about 107150 C. The

thrhigh-densityproduce is' obtained: Itis to' be-underdiiigiahfll Theremaining-volatile liquid is stiipped on froth the filter" cak'e iii the kettle; the" pharmaceutical is" withdrawn through the" valve and solidified as shown by flaking or 'casling.

This invention will be bttc r uhde'rstood by rer ience to the following examples of the treatmeiit of the ofgarlic pliarrhac e'utial acc'ordirig'" tothe process or this invention. Example Ir-Tlldtjfll'llt qf Z-nietliykZn-pfopyl prbpizhe p Li dlOldiCdlfbdMdtQ. 'K'filter cake of' -Z rnethyFZ-mproPyI-propane- 1,3 diol (teammate crystalligfed from xylol was placed-in a still anti heated to" 120 6., -l"- ab'ove itet'rue meltingpoint, at which point it was: completely liquidL= The pressure was flie'ii'redued 'to apoint at which the xylol distilled at convenient rate; maintainingthe temperature: at 120 1 30 C. by heating. As the s'olvent w'as' removed, the: was' reduced in: order to maintain the rateofdis'tillation untilthe pressure' reached 15-'-20'.mmz and the distillation ceased; The temperature 1 was maintained. The productwas removed and cast-in trays. After solidifying by cooling} the pr'oduct was broken out and g r ohnd t'o the desired particle s'izein a hammer mill;

The final product had a bulk density of 0.7' gmsrlccs after or about a" 100% i'rnprovenientlover a control dried in atmospheric shelf drier. The final product hl'ari all of the advantages listed before and none of the disadvah't'ages of the cori'trol in further tabletting operauonsl- 1 Example 2 venous other pns'raisemrens; were treated in a Sim ilar. mariner. as iii Ekaniple l. The details are presented be'low.

Mel ting Treat? Final 7, Pharmaceutical. Point, ment' Pres Solvent r C. 1 Temp, .sure', C. mm.

, E v 50Hv81. percent Betaglucosepentace- 131-132 .150 20 5 z i percent F339: IPOH. Car-brornal 116-119 128' '20 xylol':

12 15 .xylol.

65' 15 99- vol. percent ,IPOH-. Laurie acid 44 100 15 ,507}; {)POH, 50%

2 1 Diethyl stilbesteroln 169-171: 185 80 benzene. Mephenesln 69- 110 20 xylol.

In each casethe final product obtained by trleatrfidt above its melting point had increased flowability and tabletting ease., The final bulk density can be varied according to particle size desired,

4 The advantagesofthisinvention have been listed and others will be apparent to the skilled in the art. Fine organic pharmaceuticals of increased bulk density, which are more easily amenable to subsequent processing, are economically obtained. Sincethe' solvents are distilled,

. they can be completely recovered by operating the condenser at a sufiicieritlylow temperature. The'process has resulted in very substantial manufacturing savings.

It can also=be used where it is desired to screen or filter the melted liquid' to remove foreign matter prior to chilling. V

If desired; and preferably, final'traces of volatile liquid can be removed from the stripped molten pharmaceutical prior. to solidification by blowing with an inertgas such as air, nitrogen or CO under vacuum. Steam is particularly effective.

The process is advantageously applicable to materials having physiolo ical: properties, e. g.- 4-,7 dichloroquinoline; whichas Ytar'e notused as pharmaceuticals.

It is -u'nderstoodthat tl1i's inventionis notlimited to the specifi'e exampleswhiclihave been offered merely as illustrations andth'at modifications may bemade without departing from the spirit" of the invention.

What is claimed is? l;- A process for drying an organic pharmaceutical,

said organic pharmaceutical being normally solid and having a decor'riyio'sitidntenipera'tiire at least 10 C. above its melt'ing pointarid capable of being purified by crystalliia tion from a volatile liquid, which comprisesthe steps of cr'ystallizin'g thepharmaceutical from the volatile liquid, separatin and removing a'- major proportion ofthe volatile liquid-from the pharmaceutical-volatile liquid syste'mto leave'a' highconcentration of solid pharmaeeutieal in' a heterogeneous systemwiththe residual volatile liquid; stripping off remaining volatile liquid from the pharmaceutical ata temperature above the melting" point of the pharmaceutical but below its decomposition temperature, atwhich temperature the pharmaceuti'cal is liquid; cooling the stripped pharmaceutical to solidify it and then corii'minutihg it.

2. ,Theprocess ofclaim 1' in which the stripping step is" conducted at a suhatmosplierie pressure.

3. The process of claim 1 in which the volatile liquid isiafiorganic liquid.-

4. e process of claim 1 whieh the volatile liquid is water.-

5 The process ofclaim 1 in' which the pharmaceutical is dietliyl' s't ilboestr'ol.

6. The process of claim 1 in which the pharmaceutical is' niephenesin.

References Cited in the file of this patent UNITED STATES PATENTS 560,561 Zappert May 19, 1896 1,557,880 Richter Oct. 20, 1925 2,001,658 Williams May 14, 1935 2,295,745 Merriam Sept. 15, 1942 2,439,384 Fetzer Apr. 13, 1948

Claims (1)

1. A PROCESS FOR DRYING AN ORGANIC PHARMACEUTICAL, SAID ORGANIC PHARMACEUTICAL BEING NORMALLY SOLID AND HAVING A DECOMPOSITION TEMPERATURE AT LEAST 10*C. ABOVE ITS MELYING POINT AND CAPABLE OF BEING PURFIED BY CRYSTALLIZATION FROM A VOLATILE LIQID, WHICH COMPRISES THE STEPS OF CRYSTALLING THE PHARMACEUTICAL FROM THE VOLATILE LIQUID; SEPARATING AND REMOVING A MAJOR PROPORTION OF THE VOLATILE LIQUID FROM THE PHARMACEUTICAL-VOLATILE LIQUID SYSTEM TO LEAVE A HIGH CONCENTRATION OF SOLIDSPHARMEACUTICAL IN A HETERGENEOUS SYSTEM WITH THE RESIDUAL VOLATILE LIQUID; STRIPPING OFF REMAINING VOLATILE LIQUID FROM THE PHARAMEACEUTICAL AT A TEMPERATURE ABOVE THE MELTING POINT OF THE PHARMACEUTICAL BUT BELOW ITS DECOMPOSITION TEMPERATURE, AT WHICH TEMPERATURE THE PHARMACEUTICAL IS LIQUID; AT WHICH TEMPERATURE THE PHARMACEUSOLIDIFY IT AND THEN COMMINUTING IT.

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