US3313695A - Lincomycin hydrochloride crystals - Google Patents

Lincomycin hydrochloride crystals Download PDF

Info

Publication number
US3313695A
US3313695A US305816A US30581663A US3313695A US 3313695 A US3313695 A US 3313695A US 305816 A US305816 A US 305816A US 30581663 A US30581663 A US 30581663A US 3313695 A US3313695 A US 3313695A
Authority
US
United States
Prior art keywords
polymorph
lincomycin hydrochloride
capsule
lincomycin
crystals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US305816A
Inventor
Donald Ralph Van Overloop
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BE652505D priority Critical patent/BE652505A/xx
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to US305816A priority patent/US3313695A/en
Priority to CH973964A priority patent/CH486556A/en
Priority to GB30932/64A priority patent/GB1065153A/en
Priority to ES302960A priority patent/ES302960A2/en
Priority to FI1778/64A priority patent/FI42817B/fi
Priority to NL6409689A priority patent/NL6409689A/xx
Priority to AT738464A priority patent/AT257839B/en
Priority to DEU10987A priority patent/DE1207551B/en
Priority to DK426164AA priority patent/DK108966C/en
Priority to BR162250/64A priority patent/BR6462250D0/en
Priority to SE10417/64A priority patent/SE304081B/xx
Application granted granted Critical
Publication of US3313695A publication Critical patent/US3313695A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces
    • C12R2001/565—Streptomyces lincolnensis

Definitions

  • 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.
  • administration of lincomycin hydrochloride in solid form has been complicated by the low density of this material as heretofore produced.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

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.
US305816A 1961-07-03 1963-08-30 Lincomycin hydrochloride crystals Expired - Lifetime US3313695A (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BE652505D BE652505A (en) 1963-08-30
US305816A US3313695A (en) 1963-08-30 1963-08-30 Lincomycin hydrochloride crystals
CH973964A CH486556A (en) 1961-07-03 1964-07-24 Process for the preparation of modified crystalline lincomycin hydrochloride
GB30932/64A GB1065153A (en) 1963-08-30 1964-08-04 Polymorph of lincomycin hydrochloride
ES302960A ES302960A2 (en) 1963-08-30 1964-08-08 Procedure for the preparation of lincomicina (Machine-translation by Google Translate, not legally binding)
FI1778/64A FI42817B (en) 1963-08-30 1964-08-20
NL6409689A NL6409689A (en) 1963-08-30 1964-08-21
AT738464A AT257839B (en) 1961-07-03 1964-08-26 Process for the preparation of a new polymorphic form of lincomycin hydrochloride
DEU10987A DE1207551B (en) 1963-08-30 1964-08-26 Process for making high density lincomycin hydrochloride crystals
DK426164AA DK108966C (en) 1963-08-30 1964-08-28 Process for the preparation of an antibiotic, lincomycin, in the form of its hydrochloride.
BR162250/64A BR6462250D0 (en) 1963-08-30 1964-08-28 PERFECT PROCESS FOR PREPARING DENSAL CRYSTALS IN A NEW POLYMORPHIC FORM OF LINCOMYCIN CHLORIDATE
SE10417/64A SE304081B (en) 1963-08-30 1964-08-31

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US305816A US3313695A (en) 1963-08-30 1963-08-30 Lincomycin hydrochloride crystals

Publications (1)

Publication Number Publication Date
US3313695A true US3313695A (en) 1967-04-11

Family

ID=23182472

Family Applications (1)

Application Number Title Priority Date Filing Date
US305816A Expired - Lifetime US3313695A (en) 1961-07-03 1963-08-30 Lincomycin hydrochloride crystals

Country Status (10)

Country Link
US (1) US3313695A (en)
BE (1) BE652505A (en)
BR (1) BR6462250D0 (en)
DE (1) DE1207551B (en)
DK (1) DK108966C (en)
ES (1) ES302960A2 (en)
FI (1) FI42817B (en)
GB (1) GB1065153A (en)
NL (1) NL6409689A (en)
SE (1) SE304081B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050202085A1 (en) * 2000-07-08 2005-09-15 Lovercheck Dale R. Unit dose of material in system and method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050202085A1 (en) * 2000-07-08 2005-09-15 Lovercheck Dale R. Unit dose of material in system and method

Also Published As

Publication number Publication date
DK108966C (en) 1968-03-04
GB1065153A (en) 1967-04-12
ES302960A2 (en) 1964-12-01
DE1207551B (en) 1965-12-23
FI42817B (en) 1970-08-03
SE304081B (en) 1968-09-16
NL6409689A (en) 1965-03-01
BE652505A (en)
BR6462250D0 (en) 1973-08-07

Similar Documents

Publication Publication Date Title
US3683076A (en) Pharmaceutically active glucosamine salts useful in the treatment of osteoarthritis and rheumatoid arthritis
DE3143219C2 (en)
EP0212537B1 (en) Process for the preparation of a stable modification of torasemide, and medicaments containing torasemide
DE69728783T2 (en) IMPROVED MEDICINES
DE69503066T2 (en) CRYSTAL FORM OF WATER-FREE 7 - ((1a, 5a, 6a) -6-AMINO-3-AZABICYCLO (3.1.0.) HEX-3-YL) -6-FLUORO-1- (2,4-DIFLUOROPHENYL) -1, 4-DIHYDRO-4-OXO-1,8-NAPHTHYRIDINE CARBONIC ACID METHANESULFONIC ACID SALT
DE3215844A1 (en) MIXED SALT FROM GLUCOSAMINE SULFATE AND SODIUM CHLORIDE
DE69001573T2 (en) COMPOSITIONS FOR THE PRODUCTION OF D3 ACTIVE VITAMINS AND METHODS FOR THE PRODUCTION OF STABLE D3 ACTIVE VITAMINS USED THEREOF.
DE2326880C2 (en) 7- (D-α-amino-1,4-cyclohexadien-1-ylacetamido) -desacetoxycephalosporanic acid dihydrate
DE3888913T2 (en) Crystalline beta-lactam hydrate.
DE68922127T2 (en) Zinc cephiofur complexes.
US3970651A (en) Crystalline cephalosporin derivative
DE2506622C2 (en) Antibiotic drug
DE69001111T2 (en) ANTI-CANCER COMPOSITION.
US3313695A (en) Lincomycin hydrochloride crystals
DE2718730A1 (en) CEPHALOSPORIN ANTIBIOTICS
DD269850A5 (en) PROCESS FOR THE PREPARATION OF IMIDAZOLIDINE DERIVATIVES
EP0126999B1 (en) Process for making spherical crystalline 5-hydroxytetracycline hydrochloride (oxytetracycline hydrochloride)
EP0037800B1 (en) Use of o-substituted derivatives of (+)-cyanidanol-3 as compounds with immunomodulative properties
DE2557033C2 (en) Acyl derivatives of 1,2-5,6-dianhydro-dulcite, processes for their preparation and anticarcinogenic agents containing these compounds
US3585187A (en) Novel derivatives of bufadienolide-glycosides
DE3540952A1 (en) Novel 2-piperazinopteridines, processes for their preparation and medicaments containing these compounds
DE2407016C3 (en) 2-alkoxybenzoylaminocarboxylic acids, processes for their preparation and antipyretic agents containing these compounds
US2734014A (en) Glucoside colchicoside and a method of
AT257839B (en) Process for the preparation of a new polymorphic form of lincomycin hydrochloride
US3282780A (en) Lincomycin salt