DE1207551B - Process for making high density lincomycin hydrochloride crystals - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Int. α .:

A 61k

GERMAN

PATENT OFFICE

EDITORIAL

German AI .: 30 h-2/36

Number: 1 207 551

File number: U10987IV a / 30 h

Filing date: August 26, 1964

Opening day: December 23, 1965

Lincomycin is a recently discovered antibiotic that has excellent effects against certain gram-positive organisms, particularly Staphylococcus aureus, Diplococcus pneumoniae, and the beta-hemolytic streptococci. The effect of this antibiotic pathogens that cause infections have been found in both humans and animals been. However, the administration of lincomycin hydrochloride in solid form is by the the low density of the previously recoverable material made difficult. So must ζ. B. the usual single dose Lincomycin hydrochloride of the previously known crystal form, which is referred to as Polymorph I in the following in a # 00 capsule or two smaller capsules. 00 caps are generally considered by the pharmaceutical industry to be too large for use in human therapy considered; They are only used where the application of two smaller capsules represent a single dose is particularly undesirable. It has now been unexpectedly found that one second crystal form of lincomycin hydrochloride can be produced, which is a considerably higher one Having density. A full-size single dose of this substance can be placed in a # 0 capsule will. This size is generally considered acceptable by the industry and is in widely used.

The lincomycin hydrochloride or polymorph II according to the invention has a characteristic X-ray diffraction diagram on, as can be seen from the comparison of the lattice spacing of the two crystalline forms:

Grid spacing in Ä

Polymorph I Polymorph II 17.48 * 14.02 * 16.51 10.52 13.80 9.40 12.99 * 8.53 10.77 6.96 8.58 * 6.19 * 8.04 5.90 7.28 5.55 6.80 5.34 6.37 5.15 6.10 5.01 5.68 4.62 * 5.34 4.48 5.02 4.26 * Strongest gangs.

Process for the production of Lmcomycin hydrochloride crystals high density

Applicant:

The Upjohn Company, Kalamazoo, Mich.

(V. St. A.)

Representative:

Dr. W. Beil, A. Hoeppener, Dr. H. J. Wolff and Dr. H. Chr. Beil, lawyers, Frankfurt / M.- Höchst, Adelonstr. 58

Named as inventor:

Donald Ralph Van Overloop, Kalamazoo, Me.

(V. St. A.)

Claimed priority:

V. St. v. America dated August 30, 1963 (305 816)

Polymorph I Polymorph II 4.77 4.13 4.57 4.04 4.39 3.88 4.33 3.67 4.22 3.50 4.01 3.45 3.86 3.28 3.77 3.02 3.54 2.90 3.40 2.76 3.26 2.57 3.18 2.85 2.71

The XRD-5 spectrogoniometer from General Electric was used to determine the grid spacing. Cu radiation; Maximum 50 kilovolts; 16MiIIamp on X-ray tube; dual Ni filter, each 0.00889 mm thick; Passage width of the primary X-ray beam 1 °; medium resolution collimator; Passage width of the beam picked up by the detector from the sample 0.2 °; Anti-cathode angle 3 °; linear regi-

509 759/511

Claims (1)

3 4 stration; 0 to 2000 counts per second; Grid- Through laboratory tests could be shown speed 2 ° per minute. Proportional counting that the standard No. 0 capsules are only 420 mg at 1.525 kilovolts; Amplifier 8; Zl £ = 6VoIt; Lincomycin hydrochloride of crystal form I E = 3 volts (adjusted to the pulse height selector that can take, while 520 mg of lincomycin hydrodie values from the detector to the recording device 5 chloride of the new crystal form II in capsules of this transmits); Time constant 1 second. The poly size can be accommodated. The smallest morphell is hygroscopic; constant moist capsule, in which a single dose of Lincomycin Hydro- strength content 5.60%. chloride of crystal form I of 500 mg housed Polymorph I has light-colored, voluminous, needle-shaped, is the very large capsule No. 00. Crystals, whereas Polymorph II comes in small, dense hard-filled capsules containing 250 mg of lincomycin Roll the dice. The rate of solubility of hydrochloride of crystal form I and II contain Polymorph II in a test solution of 0.05 η-chlorine were as follows on a conventional capsule machine Hydrogen acid is about one and a half times the size of the one made by Polymorph I. A. Polymorph I Polymorph I crystals are quickly added 15 _T from acetone to an aqueous solution of lincomycin- ° ^ - ^a P ^is 15,000 Hydrochloride produced at low temperature. 278 mg of lincomycin hydrochloride If the aqueous solution of Lincomycm-Hydro- / qqq 1 '\ 4 yjQ Chloride, on the other hand, _{rolled at a temperature of about or 15} \ _& \ ^ _m 225 g kept above 25 ° C and acetone slowly added to the solution a. _{Lactose 75 '(. P U. S.)} / _Ge waizt \ WWlV25g added, one obtains, completely unexpectedly, ethanol 595 ε the new crystal form Polymorph II. The production _{to decrease the volume of} the drug was made the lincomycin base and the lincomycin _{hydride material moistened with ethanol and sieved} . Chloride is as specified in the sudafnkam- _{dried and iebt} _ _After ^^ _{eg carefully with} ^SC i ⁶ ^ ÄA ^r I ? ** & ΐ ^{Γ belg} ü ^C i ^en , λ ^Ρ ο ^ λ ²⁵ Talc and lactose mixed and put on the machine _{619,645 and U.S. Patent 3,086,912 in K ln ß Eg} ^^ _{a K d Nr> 0 be} . performed. _compels f Example B. Polymorph II 25 g portions of lincomycin hydrochloride were 30 per capsule dissolved in 100 cm ^{3 of} water and filtered through a Pro 15000 sintered glass filtered. For a clarified portion 278 mg lincomycin hydrochloride 1500 cm ^{3 of} acetone were quickly and without stirring (900 y / mg) 4170 g added. The mixture was left for 3 to 5 minutes for 15 mg of talc, rolled 225 g are at 5 to 10 ⁰ C; During this time, the 35,205 mg of lactose (USP), rolled 3,075 g, took place Crystallization. The crystals were filtered off, mixed with 5 mg of magnesium stearate (powdered, Acetone and washed at room temperature in the U.S.P.) 75 g Vacuum dried. This gave 22.1 g of lincomycin. The constituents were carefully mixed and Hydrochloride (Polymorph I), which is processed further on a capsule machine. For this The X-ray diffraction diagram given above was generally sufficient for the next smaller capsule size No. 1. is marked. That way, Polymorph II could be broken down into smaller ones For the other clarified portion, 1000 cm ^{3 of} hard-filled capsules were packaged, although acetone was added slowly (at a rate of 20 to three times as much lactose as the filler (at a rate of 25 cm ³ / min.) And with stirring, the increased flow) and not kept at 30 to 35 ° C for mixing. The 45 volume reduction in the ethanol treated mixture has been kept for 4 hours at this temperature. The smaller # 1 capsules can be stirred in; then the crystals were filtered off, washed lightly with acetone in most cases, even by children, and taken at room temperature.
Vacuum dried. This gave 18.1 g of lincomycin hydrochloride (Polymorph II), which was defined by the patent claim:
X-ray diffraction diagram given above is characterized. Process for the production of Lincomycin- _TT "hydrochloride crystals of high density, characterized in the production of capsule preparations that acetone is long- Capsules No. 0 are the largest, usually in ₅₅ sam, especially at a rate of 20 used in human therapy. The next to 35 cm ³ / min., To one at about 25 ° C or Larger # 00 capsules are generally considered to be kept above, especially at 30 to 35 ° C great for an application without difficulty aqueous solution of lincomycin hydrochloride see. The standard single dose for adults is added and at the same temperature up to in the majority of clinical cases carries 500 mg 6 ₀ Cessation of crystallization, especially about Lincomycin hydrochloride. For 4 hours, stir. 509 759/511 12.65 © Bundesdruckerei Berlin