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WO2004104010A1 - Crystalline form of cefdinir - Google Patents

Crystalline form of cefdinir Download PDF

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Publication number
WO2004104010A1
WO2004104010A1 PCT/IB2004/001629 IB2004001629W WO2004104010A1 WO 2004104010 A1 WO2004104010 A1 WO 2004104010A1 IB 2004001629 W IB2004001629 W IB 2004001629W WO 2004104010 A1 WO2004104010 A1 WO 2004104010A1
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WIPO (PCT)
Prior art keywords
cefdinir
salt
crystalline form
crystalline
suspension
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.)
Ceased
Application number
PCT/IB2004/001629
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French (fr)
Inventor
Yatendra Kumar
Mohan Prasad
Ashok Prasad
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.)
Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Filing date
Publication date
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Publication of WO2004104010A1 publication Critical patent/WO2004104010A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the field of the invention relates to a new crystalline form of cefdinir and processes for producing the crystalline cefdinir. More particularly, it relates to the preparation of new crystalline form of cefdinir, referred to as 'Form R' and pharmaceutical compositions that include the 'Form R'. It also relates to a method of treatment of infectious diseases comprising administration of the 'Form R'.
  • cefdinir is 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3- vinyl-3-cephem-4-carboxylic acid (syn isomer).
  • Cefdinir is a very useful antimicrobial agent, and is known from U.S. Patent No. 4,559,334.
  • Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum than other orally administrable antibiotics. Cefdinir is particularly effective against staphylococci and streptococci.
  • U.S. Patent No. 4,935,507 discloses a crystalline form, i.e. Crystal A of cefdinir characterized by its specific powder X-ray diffraction pattern and infrared spectrum.
  • the Form R may have the X-ray diffraction pattern of Figure I, infrared spectrum of Figure II and the differential scanning calorimetry plot of Figure III.
  • composition that includes a therapeutically acceptable amount of Form R of cefdinir; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a process for the preparation of Form R of cefdinir includes preparing a solution or a suspension of cefdinir or a salt thereof in water; acidifying the solution or suspension to get a mixture; stirring the mixture for a time sufficient to precipitate the crystalline Form R of cefdinir; and recovering the cefdinir in the crystalline Form R.
  • Recovering the cefdinir in the crystalline Form R includes one or more of filtration, filtration under vacuum, decantation and centrifUgation.
  • the process may include further drying of the product so obtained.
  • the process may produce the cefdinir in the crystalline Form R having a water of hydration of at least 4%.
  • the Form R may be a monohydrate of cefdinir.
  • a method of treating microbial infections in a warm-blooded animal comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form R of cefdinir.
  • Figure 1 is X- ray powder diffraction pattern of Form R of cefdinir.
  • Figure 2 is an infrared spectrum in KBr of Form R of cefdinir.
  • Figure 3 is differential scanning calorimetry plot of Form R of cefdinir.
  • the inventors have found new crystalline form of cefdinir, referred to as 'Form R'.
  • the new crystalline form is characterized by its X-ray powder diffraction pattern as shown in Figure 1 infrared spectrum as shown in Figure 2 and differential scanning calorimetry plot as shown in Figure 3.
  • the inventors also have developed process for the preparation of the new crystalline form of cefdinir, by preparing a solution or a suspension of cefdinir or a salt thereof; acidifying the solution or suspension to get a mixture; stirring the mixture for a time sufficient to precipitate the crystalline Form R of cefdinir; and recovering the cefdinir in the crystalline Form R.
  • the inventors also have developed pharmaceutical composition that contain Form R of the cefdinir, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
  • crystalline Form R of cefdinir is characterized by X-ray peaks at about 11.72, 18.58, 20.92, 21.2, 22.28, 24.42, and 26.24 degrees two-theta and infrared spectral bands at about 1015, 1049, 1135, 1190, 1350, 1543, 1610, and 1667 cm "1 .
  • the solution or suspension of cefdinir may be obtained by dissolving cefdinir or a salt thereof in water.
  • such a solution may be obtained directly from a reaction in which cefdinir is formed.
  • the process for preparing crystalline form R of cefdinir can be carried out at a temperature of about 10 °C or lower temperatures, for example from about 10 °C to about - 10 °C. More particularly, it can be carried out at a temperature from about 5 °C to about -5°C.
  • the acidification process can be carried out by adding an inorganic or an organic acid.
  • suitable acids include inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids, and organic acids such as trifluoroacetic, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and formic acids.
  • the acid is added in an amount that makes the pH value of the solution/suspension from about 0.5 to about 4, for example, from about 1.5 to about 3.
  • the concentration of the solution/suspension of the salt of cefdinir can be in the range from about 1% to about 20% by weight, for example, from about 3% to about 10% by weight.
  • the mixture may be stirred for a time sufficient to precipitate crystalline Form R of cefdinir.
  • the duration can be from about 1 hour to about 15 hours in general and may vary depending on the temperature, the concentration, as also whether the starting salt is in solution or suspension.
  • the precipitation of the crystalline Form R from a solution may require stirring for a longer duration in general, for example from about 5 hours to about 15 hours.
  • Suitable salts of cefdinir that can be used in the process are conventional non-toxic l salts and may include a salt with an inorganic base, for example an alkali metal salt, such as sodium and potassium salts; an alkaline earth metal salt, such as calcium and magnesium salts; an ammonium salt; a salt with an organic base, for example, an organic amine salt such as, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, and dicyclohexylamine salts.
  • an inorganic base for example an alkali metal salt, such as sodium and potassium salts
  • an alkaline earth metal salt such as calcium and magnesium salts
  • an ammonium salt such as, a salt with an organic base, for example, an organic amine salt such as, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, and dicyclohexylamine salts.
  • the salts of cefdinir may be obtained by methods known in the art including those described in U.S. Patent No. 4,559,334.
  • the crystalline potassium salt of cefdinir was prepared according to the process disclosed in our co-pending PCT Patent Application Serial No. PCT/TB02/05315.
  • the salts of cefdinir may also be obtained by adding a base to a suspension of cefdinir in water.
  • bases include alkali metal salts of carboxylic acids, such as sodium acetate and potassium acetate; organic amines, such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, ammonium hydroxide, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, and alkali metal bicarbonates, such as sodium bicarbonate.
  • Cefdinir may be prepared using the reactions and techniques known in the art including those described in U.S. Patent Nos. 4,559,334; 4,870,168; and 6,093,814; WO , 92/7840; and PCT Patent Application Serial No. PCT/IB02/01410.
  • the precipitated crystalline Form R of cefdinir may be recovered by conventional methods such as filtration, filtration under vacuum, decantation and centrifugation.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the crystalline Form R of cefdinir is pure, easy to handle, stable against heat and light, and is at least as free of residual solvents as the starting cefdinir. It is thus, suitable for pharmaceutical preparations and in storage.
  • cefdinir of crystalline Form R can be administered for the treatment of microbial infections, such as skin respiratory and urinary tract infections in a warm-blooded animal.
  • cefdinir of crystalline Form R may be used for treating community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • the cefdinir Form R can be administered by any conventional means alone or in combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected in the basis of the chosen route of administration and standard pharmaceutical practice.
  • the cefdinir Form R may be formulated into ordinary dosage forms such as, for example, tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • Crystalline cefdinir potassium salt (5.0 g) was suspended in water (150ml) at 3 - 4°C. pH of this heterogeneous mixture was adjusted to 2.4 to 2.6 at 3 to 4°C using 3N hydrochloric acid. The mixture was stirred for 5 to 6 hours maintaining temperature at 3 to 4°C. The precipitated solid was filtered and dried under vacuum at 40 to 45°C to get 4.0 g of off-white crystalline Form R of cefdinir.
  • Cefdinir free acid (5.0 g) was suspended in water at ambient temperature. pH of this heterogeneous mixture was adjusted to 6.0 to 6.5 with sodium bicarbonate for complete dissolution. Undissolved particulate matter was filtered off. The clear solution was cooled to 2 to 5°C. pH was adjusted to isoelectric point of cefdinir with 3N hydrochloric acid at 2 to 5°C. The mixture was stirred for 8 to 10 hours maintaining temperature at 2 to 5°C to grow form R of cefdinir. The precipitated solid was filtered and dried under vacuum at 40 to 45°C to get 3.8 g of off-white crystalline Form R of cefdinir.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention relates to a new crystalline form of cefdinir and processes for producing the crystalline cefdinir. More particularly, it relates to the preparation of new crystalline form of cefdinir, referred to as 'Form R' and pharmaceutical compositions that include the 'Form R'. It also relates to a method of treatment of infectious diseases comprising administration of the 'Form R'.

Description

CRYSTALLINE FORM OF CEFDINIR
Field of the Invention
The field of the invention relates to a new crystalline form of cefdinir and processes for producing the crystalline cefdinir. More particularly, it relates to the preparation of new crystalline form of cefdinir, referred to as 'Form R' and pharmaceutical compositions that include the 'Form R'. It also relates to a method of treatment of infectious diseases comprising administration of the 'Form R'.
Background of the Invention
Chemically, cefdinir is 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3- vinyl-3-cephem-4-carboxylic acid (syn isomer). Cefdinir is a very useful antimicrobial agent, and is known from U.S. Patent No. 4,559,334. Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum than other orally administrable antibiotics. Cefdinir is particularly effective against staphylococci and streptococci. U.S. Patent No. 4,935,507 discloses a crystalline form, i.e. Crystal A of cefdinir characterized by its specific powder X-ray diffraction pattern and infrared spectrum.
Summary of the Invention
hi one general aspect there is provided a crystalline form of cefdinir, 'Form R'.
The Form R may have the X-ray diffraction pattern of Figure I, infrared spectrum of Figure II and the differential scanning calorimetry plot of Figure III.
In another general aspect there is provided a pharmaceutical composition that includes a therapeutically acceptable amount of Form R of cefdinir; and one or more pharmaceutically acceptable carriers, excipients or diluents.
hi another general aspect there is provided a process for the preparation of Form R of cefdinir. The process includes preparing a solution or a suspension of cefdinir or a salt thereof in water; acidifying the solution or suspension to get a mixture; stirring the mixture for a time sufficient to precipitate the crystalline Form R of cefdinir; and recovering the cefdinir in the crystalline Form R. Recovering the cefdinir in the crystalline Form R includes one or more of filtration, filtration under vacuum, decantation and centrifUgation.
The process may include further drying of the product so obtained.
The process may produce the cefdinir in the crystalline Form R having a water of hydration of at least 4%. In particular, the Form R may be a monohydrate of cefdinir.
In another general aspect there is provided a method of treating microbial infections in a warm-blooded animal, the method comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form R of cefdinir.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Description of the Drawings
Figure 1 is X- ray powder diffraction pattern of Form R of cefdinir.
Figure 2 is an infrared spectrum in KBr of Form R of cefdinir.
Figure 3 is differential scanning calorimetry plot of Form R of cefdinir.
Detailed Description of the Invention
The inventors have found new crystalline form of cefdinir, referred to as 'Form R'. The new crystalline form is characterized by its X-ray powder diffraction pattern as shown in Figure 1 infrared spectrum as shown in Figure 2 and differential scanning calorimetry plot as shown in Figure 3. The inventors also have developed process for the preparation of the new crystalline form of cefdinir, by preparing a solution or a suspension of cefdinir or a salt thereof; acidifying the solution or suspension to get a mixture; stirring the mixture for a time sufficient to precipitate the crystalline Form R of cefdinir; and recovering the cefdinir in the crystalline Form R. The inventors also have developed pharmaceutical composition that contain Form R of the cefdinir, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients. In general crystalline Form R of cefdinir is characterized by X-ray peaks at about 11.72, 18.58, 20.92, 21.2, 22.28, 24.42, and 26.24 degrees two-theta and infrared spectral bands at about 1015, 1049, 1135, 1190, 1350, 1543, 1610, and 1667 cm"1.
In general, the solution or suspension of cefdinir may be obtained by dissolving cefdinir or a salt thereof in water. Alternatively, such a solution may be obtained directly from a reaction in which cefdinir is formed.
The process for preparing crystalline form R of cefdinir can be carried out at a temperature of about 10 °C or lower temperatures, for example from about 10 °C to about - 10 °C. More particularly, it can be carried out at a temperature from about 5 °C to about -5°C.
The acidification process can be carried out by adding an inorganic or an organic acid.
Examples of suitable acids include inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids, and organic acids such as trifluoroacetic, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and formic acids.
The acid is added in an amount that makes the pH value of the solution/suspension from about 0.5 to about 4, for example, from about 1.5 to about 3.
The concentration of the solution/suspension of the salt of cefdinir can be in the range from about 1% to about 20% by weight, for example, from about 3% to about 10% by weight.
After acidification, the mixture may be stirred for a time sufficient to precipitate crystalline Form R of cefdinir. The duration can be from about 1 hour to about 15 hours in general and may vary depending on the temperature, the concentration, as also whether the starting salt is in solution or suspension. The precipitation of the crystalline Form R from a solution may require stirring for a longer duration in general, for example from about 5 hours to about 15 hours.
Suitable salts of cefdinir that can be used in the process are conventional non-toxic l salts and may include a salt with an inorganic base, for example an alkali metal salt, such as sodium and potassium salts; an alkaline earth metal salt, such as calcium and magnesium salts; an ammonium salt; a salt with an organic base, for example, an organic amine salt such as, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, and dicyclohexylamine salts.
The salts of cefdinir may be obtained by methods known in the art including those described in U.S. Patent No. 4,559,334. In particular, the crystalline potassium salt of cefdinir was prepared according to the process disclosed in our co-pending PCT Patent Application Serial No. PCT/TB02/05315.
The salts of cefdinir may also be obtained by adding a base to a suspension of cefdinir in water. Examples of bases include alkali metal salts of carboxylic acids, such as sodium acetate and potassium acetate; organic amines, such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, ammonium hydroxide, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, and alkali metal bicarbonates, such as sodium bicarbonate.
Cefdinir may be prepared using the reactions and techniques known in the art including those described in U.S. Patent Nos. 4,559,334; 4,870,168; and 6,093,814; WO , 92/7840; and PCT Patent Application Serial No. PCT/IB02/01410.
The precipitated crystalline Form R of cefdinir may be recovered by conventional methods such as filtration, filtration under vacuum, decantation and centrifugation.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
The crystalline Form R of cefdinir is pure, easy to handle, stable against heat and light, and is at least as free of residual solvents as the starting cefdinir. It is thus, suitable for pharmaceutical preparations and in storage.
The cefdinir of crystalline Form R can be administered for the treatment of microbial infections, such as skin respiratory and urinary tract infections in a warm-blooded animal. In particular, cefdinir of crystalline Form R may be used for treating community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections. For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
The cefdinir Form R can be administered by any conventional means alone or in combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected in the basis of the chosen route of administration and standard pharmaceutical practice.
The cefdinir Form R may be formulated into ordinary dosage forms such as, for example, tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Methods
X-Ray Powder Diffraction
X-ray powder diffraction patterns were recorded using the following instrument and parameters:
X-Ray Difractometer, Rigaku Coorperation, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1 0 Power: 40 KV, 100 mA
Scanning speed: 2 deg/min step: 0.02 deg
Wave length: 1.5406 A
Infrared Spectra Infrared spectra were recorded using the following instrument and parameters: hιstrument:Perkin Elmer, 16 PC
SCAN: 16 scans, 4.0 cm"1
According to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
Differential Scanning Calorimetry
Differential scanning calorimetry plots were recorded using the following instrument and parameters:
DSC821 e, Mettler Toledo
Sample weight: 3-5 mg Temperature range: 25-100° C
Heating rate: 1° C/min
Nitrogen 80.0 mL/min
Number of holes in the crucible: 1
Example 1
Crystalline cefdinir potassium salt (5.0 g) was suspended in water (150ml) at 3 - 4°C. pH of this heterogeneous mixture was adjusted to 2.4 to 2.6 at 3 to 4°C using 3N hydrochloric acid. The mixture was stirred for 5 to 6 hours maintaining temperature at 3 to 4°C. The precipitated solid was filtered and dried under vacuum at 40 to 45°C to get 4.0 g of off-white crystalline Form R of cefdinir.
HPLC Purity = 99.59 %, Moisture Content (% w/w by KF) = 4.55 %.
XRD, IR, and DSC spectra were similar to those shown in Figure I, II and III, respectively. Example 2
Cefdinir free acid (5.0 g) was suspended in water at ambient temperature. pH of this heterogeneous mixture was adjusted to 6.0 to 6.5 with sodium bicarbonate for complete dissolution. Undissolved particulate matter was filtered off. The clear solution was cooled to 2 to 5°C. pH was adjusted to isoelectric point of cefdinir with 3N hydrochloric acid at 2 to 5°C. The mixture was stirred for 8 to 10 hours maintaining temperature at 2 to 5°C to grow form R of cefdinir. The precipitated solid was filtered and dried under vacuum at 40 to 45°C to get 3.8 g of off-white crystalline Form R of cefdinir.
HPLC Purity = 99.15 %, Moisture Content (% w/w by KF) = 6.19 %.
XRD, IR, and DSC spectra were similar to those shown in Figure I, II and III, respectively.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim:
1. 'Form R' crystalline cefdinir.
2. The Form R of claim 1 , wherein the cefdinir has the X-ray diffraction pattern of Figure 1.
/ 3. The Form R of claim 1, wherein the cefdinir has the infrared spectrum of Figure 2.
4. The Form R of claim 1, wherein the cefdinir has the differential scanning calorimetry plot of Figure 3.
5. The Form R of claim 1 , which is an off-white crystalline powder.
6. A crystalline Form R of cefdinir characterized by X-ray diffraction pattern having ' peaks at about 11.72, 18.58, 20.92, 21.2, 22.28, 24.42, and 26.24 degrees 2-theta.
7. A crystalline Form R of cefdinir characterized by infrared spectral bands at about 1015, 1049, 1135, 1190, 1350, 1543, 1610, and 1667 cm"1.
8. A crystalline Form R of cefdinir, characterized by a water of hydration of at least 4%.
9. The crystalline form of claim 8, which is a monohydrate of cefdinir.
10. A pharmaceutical composition comprising:
a therapeutically effective amount of Form R cefdinir;
and one or more pharmaceutically acceptable carriers, excipients or diluents.
11. The phannaceutical composition of claim 10, wherein the cefdinir has the X-ray diffraction pattern of Figure 1.
12. The pharmaceutical composition of claim 10, wherein the cefdinir has the infrared spectrum of Figure 2.
13. The pharmaceutical composition of claim 10, wherein the cefdinir has the differential scanning calorimetry plot of Figure 3.
14. A process for the preparation of crystalline Form R of cefdinir, the process comprising:
preparing a solution or a suspension of cefdinir or a salt thereof in water;
acidifying the solution or suspension at a temperature of from about -10°C to about 10°C to get a mixture;
stirring the mixture for a time sufficient to precipitate the crystalline Form R; and
recovering the cefdinir in the crystalline Form R.
15. The process of claim 14, wherein the temperature is from about -5°C to
about 5°C.
16. The process of claim 14, wherein the solution or suspension is acidified to a pH value of from about 0.5 to about 4.
17. The process of claim 16, wherein the pH value is from about 1.5 to about 3.
18. The process of claim 14, wherein the salt of cefdinir is obtained by adding a base to a suspension of cefdinir in water.
19. The process of claim 14 or 18, wherein cefdinir or its salt is obtained as a solution directly from a reaction in which cefdinir is formed.
20. The process of claim 14, wherein the salt of cefdinir is a salt with an inorganic base.
21. The process of claim 20, wherein the salt is an alkali metal salt, an alkaline earth metal salt or an ammonium salt.
22. The process of claim 21 , wherein the alkali metal salt is a sodium or potassium salt.
23. The process of claim 14, wherein the salt of cefdinir is a salt with an organic base.
24. The process of claim 23, wherein the salt is a triethylamine, pyridine, picoline, ethanolamine, triethanolamine, or dicyclohexylamine salt of cefdinir.
25. The process of claim 14, further comprising additional drying of the product obtained.
26. The process of claim 14, further comprising forming the product obtained into a finished dosage form.
27. The process of claim 14, wherein the cefdinir has the X-ray diffraction pattern of Figure 1.
28. The process of claim 14, wherein the cefdinir has the infrared spectrum of Figure 2.
29. The process of claim 14, wherein the cefdinir has the differential scanning calorimetry plot of Figure 3.
30. A method for treating microbial infections in a warm-blooded animal comprising administering a pharmaceutical composition that includes a crystalline Form R of cefdinir.
31. The method of claim 30, wherein the microbial infection is a skin respiratory or a urinary tract infection.
32. The method of claim 30, wherein the microbial infection is a community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, and uncomplicated skin and skin structure infection.
PCT/IB2004/001629 2003-05-20 2004-05-20 Crystalline form of cefdinir Ceased WO2004104010A1 (en)

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IN711DE2003 2003-05-20
IN711/DEL/2003 2003-05-20

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WO2005090360A1 (en) * 2004-03-19 2005-09-29 Orchid Chemicals & Pharmaceuticals Limited Novel polymorph of cefdinir
WO2006018807A1 (en) * 2004-08-16 2006-02-23 Ranbaxy Laboratories Limited Crystalline forms of cefdinir
WO2006059753A1 (en) * 2004-11-30 2006-06-08 Astellas Pharma Inc. Novel oral pharmaceutical suspension of cefdinir crystal
GB2421024A (en) * 2004-12-07 2006-06-14 Sandoz Ag Cefdinir crystalline form C
WO2006117794A1 (en) * 2005-05-02 2006-11-09 Hetero Drugs Limited A novel crystalline form of cefdinir
WO2007008674A1 (en) * 2005-07-08 2007-01-18 Abbott Laboratories Crystalline cefdinir hydrates
EP1795197A1 (en) * 2005-12-07 2007-06-13 Sandoz AG Pharmaceutical compositions comprising an antibiotic
US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
WO2007053723A3 (en) * 2005-10-31 2007-09-13 Teva Pharma Process for the preparation of cefdinir
EP1899356A1 (en) * 2005-06-15 2008-03-19 Hetero Drugs Limited Cefdinir process
JP2008525531A (en) * 2005-10-31 2008-07-17 テバ ファーマシューティカル インダストリーズ リミティド Crystalline form of cefdinir potassium salt
JP2008526782A (en) * 2005-10-31 2008-07-24 テバ ファーマシューティカル インダストリーズ リミティド Cefdinir cesium salt crystals
WO2011078827A1 (en) * 2009-12-25 2011-06-30 Bilgic Mahmut The production method for effervescent tablet with cefdinir
WO2011078830A1 (en) * 2009-12-25 2011-06-30 Bilgic Mahmut Rapidly dispersing effervescent formulation
WO2011093821A1 (en) * 2010-01-29 2011-08-04 Mahmut Bilgic Effervescent formulations comprising cefdinir and clavulanic acid
WO2011139249A3 (en) * 2010-05-04 2012-03-01 Mahmut Bilgic Pharmaceutical composition comprising cefdinir
US8614315B2 (en) 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof

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US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7825241B2 (en) 2002-08-13 2010-11-02 Sandoz Ag Cefdinir intermediate
WO2005090360A1 (en) * 2004-03-19 2005-09-29 Orchid Chemicals & Pharmaceuticals Limited Novel polymorph of cefdinir
WO2006018807A1 (en) * 2004-08-16 2006-02-23 Ranbaxy Laboratories Limited Crystalline forms of cefdinir
US7351419B2 (en) 2004-11-30 2008-04-01 Astellas Pharma Inc. Oral pharmaceutical suspension of Cefdinir crystal
WO2006059753A1 (en) * 2004-11-30 2006-06-08 Astellas Pharma Inc. Novel oral pharmaceutical suspension of cefdinir crystal
US7307072B2 (en) * 2004-11-30 2007-12-11 Astellas Pharma Inc. Oral pharmaceutical suspension of Cefdinir crystal
GB2421024A (en) * 2004-12-07 2006-06-14 Sandoz Ag Cefdinir crystalline form C
WO2006117794A1 (en) * 2005-05-02 2006-11-09 Hetero Drugs Limited A novel crystalline form of cefdinir
EP1899356A1 (en) * 2005-06-15 2008-03-19 Hetero Drugs Limited Cefdinir process
WO2007008674A1 (en) * 2005-07-08 2007-01-18 Abbott Laboratories Crystalline cefdinir hydrates
WO2007053723A3 (en) * 2005-10-31 2007-09-13 Teva Pharma Process for the preparation of cefdinir
JP2008524265A (en) * 2005-10-31 2008-07-10 テバ ファーマシューティカル インダストリーズ リミティド Method for producing cefdinir
JP2008525531A (en) * 2005-10-31 2008-07-17 テバ ファーマシューティカル インダストリーズ リミティド Crystalline form of cefdinir potassium salt
JP2008526782A (en) * 2005-10-31 2008-07-24 テバ ファーマシューティカル インダストリーズ リミティド Cefdinir cesium salt crystals
WO2007053724A3 (en) * 2005-10-31 2008-11-06 Teva Pharma Crystalline forms of cefdinir potassium salt
EP1795197A1 (en) * 2005-12-07 2007-06-13 Sandoz AG Pharmaceutical compositions comprising an antibiotic
WO2011078827A1 (en) * 2009-12-25 2011-06-30 Bilgic Mahmut The production method for effervescent tablet with cefdinir
WO2011078830A1 (en) * 2009-12-25 2011-06-30 Bilgic Mahmut Rapidly dispersing effervescent formulation
WO2011078831A1 (en) * 2009-12-25 2011-06-30 Mahmut Bilgic Improved pharmaceutical compositions comprising cefdinir
WO2011078822A1 (en) * 2009-12-25 2011-06-30 Mahmut Bilgic Pharmaceutical compositions comprising cefdinir as an active agent
US8614315B2 (en) 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
WO2011093821A1 (en) * 2010-01-29 2011-08-04 Mahmut Bilgic Effervescent formulations comprising cefdinir and clavulanic acid
WO2011093827A1 (en) * 2010-01-29 2011-08-04 Mahmut Bilgic Water dispersible cefdinir and clavulanic acid formulations for treatment of bacterial infections
WO2011139249A3 (en) * 2010-05-04 2012-03-01 Mahmut Bilgic Pharmaceutical composition comprising cefdinir
WO2011139252A3 (en) * 2010-05-04 2012-03-01 Mahmut Bilgic Efervescent formulations comprising cefdinir

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