US3313695A - Lincomycin hydrochloride crystals - Google Patents

Description

United States Patent 3,313,695 LINCUMYCIN HYDRQCHLORIDE CRYSTALS Donald Ralph Van Overloop, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed Aug. 30, 1963, Ser. No. 305,816 1 Claim. (Cl. 167-65) This invention relates to a new polymorph of lincomycin hydrochloride.

Lincomycin is a recently discovered antibiotic demonstrating pronounced activity against certain gram positive organisms, including especially Staphylococcus aureus, Diplococczls pneumonz'ae, and the beta hemolytic streptococci. The effectiveness of this antibiotic has been demonstrated in humans and animals against infections due to susceptible pathogens. However, administration of lincomycin hydrochloride in solid form has been complicated by the low density of this material as heretofore produced. For example, the preferred single dose of lincomycin hydrochloride of the known crystalline form, hereinafter designated polymorph I, requires administration either of a No. 00 capsule or two capsules of smaller sizes. The No. 00 capsule is generally regarded in the pharmaceutical industry as too large for human use and is only employed where it is particularly undesirable to present the medication in two smaller capsules constituting a single dose.

It has been unexpectedly found that a second crystalline form, or polymorph, of lincomycin hydrochloride can be produced which displays a significantly higher density and enables the single preferred dose to be incorporated in a No. 0 capsule. This size is generally regarded as acceptable in the industry and is widely employed.

Polymorph II displays a distinctive X-ray diffraction pattern, as indicated in the following comparison of interplanar spacings as obtained on X-ray diffraction of the two crystalline forms:

Interplanar spacings A Polymorph I Polymorph II I) Polymorph I Polymorph II 1 Major peaks.

The General Electric XRD-S spectrogoniometer was used. (Cu radiation, 50 kvp., 16 ma., 2 Ni filter, 1 slit beam, MR soller, 0.2 detector slit, chart range linear 2000 c.p.s., 2 per minute scan, No. 6 SPG proportional counter 1.525 kv., gain 8, AB 6 volts, E 3 volts, time constant 1 second, target angle 3.) Polymorph II is hygroscopic. Constant moisture content: 5.60%.

Polymorph I is characterized as light, bulky, needlelike crystals, whereas polymorph lI exists as small, dense cubes. The solution rate of polymorph II in a test solution of 0.05 N hydrochloric acid is about 1 /2 times that of polymorph I.

Polymorph I is prepared by producing crystals through rapid addition of acetone to an aqueous solution of lincomycin hydrochloride at reduced temperature. Un-

Patented Apr. 11, 1967 expectedly, however, the advantageous polymorph II is formed when the acetone is added slowly and the temperature of the aqueous solution of lincomycin hydrochloride is maintained at or above about 25 C. Preparation of the lincomycin base and hydrochloride follows the methods described in Republic of SouthAfrica Patent No. 2184/62, Belgian Patent No. 619,645 and U.S. Patent No. 3,086,912.

The following preparations and examples illustrate the production of the product of this invention and its pharmaceutical formulation but are not to be construed as limiting.

Example 1 Twenty-five gram aliquots of lincomycin hydrochloride were dissolved in ml. of water and filtered through sintered glass. To one clarified aliquot was added 1500 ml. of acetone quickly and without stirring. The mixture was allowed to stand 3-5 minutes while maintained at 510 C., during which time crystallization took place. The crystals were removed by filtration, washed with acetone, and vacuum-dried at room temperature to give 22.1 gm. of lincomycin hydrochloride (polymorph I) characterized by the X-ray diffraction pattern given above.

To the other clarified aliquot from above was added 1000 ml. of acetone slowly (at a rate of 20-25 ml. per minute) and the mixture maintained at 30-35 C. with stirring. After stirring for four hours at that temperature, the crystals were removed by filtration, washed with acetone and vacuum-dried at room temperature to give 18.1 gm. of lincomycin hydrochloride (polymorph 11) char acterized by the X-ray diffraction pattern given above.

Example 2Capsules Capsules of No. 0 size are the largest capsules in common use for human therapy. The No. 00 size (next larger) is generally regarded as too large for convenient administration. The standard single adult dose of lincomycin hydrochloride is 500 mg. for the majority of clinical indications.

Laboratory studies showed that a standard No. 0 capsule can contain only 420 mg. of the known polymorph I of lincomycin hydrochloride, whereas the standard No. 0 capsule can contain 520 mg. of the new polymorph II of lincomycin hydrochloride. The smallest capsule that will contain a single, 500 mg. dose of lincomycin hydrochloride polymorph I is the excessively large No. 00.

Example 3-Capsules Hard filled capsules containing 250 mg. of l-incomycin hydrochloride, polymorphs I and II, were prepared as follows on production capsulating machines.

(A) POLYMORPH I In order to reduce the bulk of the drug, it was wetted with the ethanol, screened, dried and screened. Finally, it was mixed thoroughly with the tale and lactose and capsulated by machine. A No. 0 capsule was required.

(B) POLYMOBPH 11 Per Per Capsule 15,000

(rng.) Capsules Lincomycin hydrochloride (Assay 900 mcg./mg.) 278 4, 170 Talc, bolted 15 225 Lactose U.S.P., bolted s 205 3, 075 Magnesium stearate Po., U.S.P 5 75 The ingredients were mixed thoroughly and capsulated by machine. The smaller No. 1 capsule was adequate for this charge.

Thus polymorph 11 could be packed into a smaller hard [filled capsule even though it contained three times as much lactose as filler (to increase fiowability) and Was not treated with ethanol to reduce bulk. The smaller No. .1 capsule can be swallowed more readily by most children.

What is claimed is:

A new polymorphic form of lincomycin hydrochloride,

the crystals of which are characterized by the following X-ray diffraction pattern:

Inter-planar spacings, A

1 Major peaks.

No references cited.

SAM ROSEN, Primary Examiner.