EP1180022A1 - Elaboration d'un produit pharmaceutique en vrac uniformement dissout - Google Patents

Elaboration d'un produit pharmaceutique en vrac uniformement dissout

Info

Publication number
EP1180022A1
EP1180022A1 EP99927538A EP99927538A EP1180022A1 EP 1180022 A1 EP1180022 A1 EP 1180022A1 EP 99927538 A EP99927538 A EP 99927538A EP 99927538 A EP99927538 A EP 99927538A EP 1180022 A1 EP1180022 A1 EP 1180022A1
Authority
EP
European Patent Office
Prior art keywords
cefaclor
water content
capsule
water
minutes
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.)
Withdrawn
Application number
EP99927538A
Other languages
German (de)
English (en)
Other versions
EP1180022A4 (fr
Inventor
Frank Brown, Jr.
Robert Alan Forbes
Arlette Faye Kreager
Michael Vincent Mullen
Gregory Alan Stephenson
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and 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
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1180022A1 publication Critical patent/EP1180022A1/fr
Publication of EP1180022A4 publication Critical patent/EP1180022A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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

Definitions

  • the present invention relates to a process for preparing a pharmaceutical bulk material having more uniform dissolution in water, in particular, uniform dissolution of cefaclor bulk material.
  • Cefaclor (3-chloro-7-D- (phenylglycinamido) -3-cephem- 4-carboxylic acid) is a semi-synthetic, second- generation, cephalosporin antibiotic. Cephalosporins exert their antibacterial activity by reacting with and thereby inactivating one or more of the penicillin- binding proteins located in the bacterial cell wall. Cefaclor is active against a wide range of commonly found pathogens, including S. aureus, ⁇ -haemolytic streptococci pneumonococci, Haemophil us infl uenzae, E. coli , Klebsiella pneumoniae and Proteus mirabilis .
  • cefaclor forms currently available for oral administration of cefaclor include capsules, retard tablets and suspension (both in vial and sachet form) .
  • the USP standard for cefaclor capsules requires at least 80% (Q) of the capsule to dissolve in water in 30 minutes.
  • the dissolution rate is dependent upon the solubility of the active ingredient (s) as well as the excipients used in the formulation and ingredients used in the formation of the capsule.
  • capsules prepared from freshly prepared cefaclor onohydrate bulk materials do not consistently meet the USP standard; however, capsules prepared from aged cefaclor monohydrate bulk materials more consistently meet the USP standards.
  • acceptable product can be produced from aged materials, the aging process causes several disadvantages. For example, the material is not available for use over an extended period of time, storage costs, and lot to lot variability over time. Therefore, there is a need to provide a process that produces capsules having more uniform and consistent dissolution rates without having to age the bulk active material.
  • the present invention provides a process for producing cefaclor crystalline bulk form having a dissolution rate in a capsule of > 80% in water in 30
  • the material produced having a water content ⁇ 2% may be any material produced having a water content ⁇ 2%.
  • cefaclor material having a dissolution rate in a capsule of ⁇ 80% in water in 30
  • minutes at 37°C may be characterized by: the presence of a near infrared reflectance (NIR) absorbance at 5798 cm -1 (1725 rim) either initially or within 5 minutes after the addition of water to the sample (i.e., NIR onset time ⁇ 5 minutes); having a non-homogenous water content (e.g., lots containing residual dihydrate starting materials) ; or agglomerates upon addition of water.
  • NIR near infrared reflectance
  • Crystalline cefaclor bulk materials and capsules prepared therefrom having a dissolution rate in a capsule of > 80% in water in 30 minutes at 37°C prepared by the processes described above are also provided.
  • cefaclor crystalline bulk form or “cefaclor crystalline bulk material” refers to a mixture of a non-stoichiometric cefaclor monohydrate and anhydrous cefaclor.
  • NIR onset time refers to the time between addition of water to a cefaclor sample and the observation of an absorption peak at about 5798 cm -1 (1725 run) as measured by Near-Infrared Reflectance Spectroscopy (NIRS) . Depending upon the particular instrument used, the exact peak measurement may vary within the standard deviation established for that particular instrument.
  • Cefaclor related substances refers to degradation products of cefaclor that are structurally related to the pharmaceutically active cefaclor compound.
  • related substances include compounds such as the ⁇ 2- isomer of cefaclor, the decarboxylated derivative of cefaclor, and other similar degradation products.
  • FIGURES Figure 1 illustrates the HPLC chromatograms (UV detection, 220 nm) of preparative HPLC fractions 1-4 overlaid with the chromatogram from the 85°C-degraded sample.
  • Figure 2 illustrates the HPLC chromatograms (UV detection, 220 nm) of preparative HPLC fractions 5-7 overlaid with the chromatogram from the 85°C-degraded sample.
  • cefaclor bulk the product is crystallized from an aqueous system as a dihydrate crystal form.
  • the cefaclor dihydrate is then converted to the cefaclor crystalline bulk form (mixture of a non-stoichiometric cefaclor monohydrate and anhydrous cefaclor) by partially removing water (e.g., fluid bed dryer) from the dihydrate crystalline material.
  • XRD X-ray diffraction
  • the change in dissolution rate is caused by the crystal form transformation of the cefaclor bulk back to the dihydrate form.
  • the dihydrate form is less readily soluble in water than the monohydrate form.
  • An accelerated conversion of the monohydrate to the dihydrate form upon exposure to water is believed to cause the formulated material to agglomerate into a hard plug of material in the dissolution testing apparatus, thus inhibiting it from dispersing and dissolving.
  • the conversion rate of the monohydrate to the dihydrate form has been shown to be enhanced by increasing the concentration of amorphous cefaclor and/or dihydrate seeds, and inhibited by increasing the concentration of cefaclor related substances.
  • cefaclor bulk material having an improved dissolution rate in capsules. It is believed that the additional drying process removes traces of cefaclor dihydrate thus reducing the potential for seeding crystallization of the dihydrate form.
  • the material can be surprisingly rehydrated to a water content from about 3.0 to about 6.5% (preferably from about 3.0% to 5.0%, more preferably from about 3.0% to 4.5%) without causing the material to fail the dissolution test.
  • a dissolution model test was developed for capsules filled in the laboratory with the drug substance only.
  • a second test was developed to qualitatively determine the tendency of a bulk lot to agglomerate when wetted (aqueous dispersability test) .
  • a test was ultimately developed using Near-Infrared Reflectance Spectroscopy (NIRS) .
  • NIRS Near-Infrared Reflectance Spectroscopy
  • NIRS readily distinguishes between the dihydrate, monohydrate, and anhydrate forms of cefaclor.
  • the dihydrate form has a relatively strong absorbance at about 5798 cm -1 which provides an excellent indicator for the presence of the dihydrate form in the sample.
  • the NIRS conversion test measures the time in minutes before the onset of the crystal form reversion for a sample of cefaclor bulk.
  • the NIR onset time was found to be an indicator of the dissolution assay result for a given bulk lot. Lots exhibiting longer NIR onset times ( > about 5 minutes) were less likely to agglomerate during the dissolution test, whereas lots with short NIR onset times ( ⁇ about 5 minutes) were more likely to revert to the dihydrate during the dissolution test, forming a plug of non-dispersing agglomerated material prior to complete dissolution of the capsule shell. To ensure that a lot will have an acceptable dissolution rate, one generally strives for a NIR onset time of > 7 minutes, preferably > 9 minutes and more preferably > 10 minutes.
  • the dihydrate reversion time was found to be delayed or the reversion altogether inhibited by addition of cefaclor related substances to a cefaclor bulk sample; whereas, the addition of amorphous cefaclor and/or cefaclor dihydrate was found to decrease the reversion onset time thus accelerating the crystal form conversion.
  • amorphous cefaclor and/or cefaclor dihydrate can be explained by a classical crystallization model: 1) additional amorphous cefaclor increases the level of cefaclor supersaturation in a wetted sample; 2) the dihydrate serves as a source of seed for the recrystallization as dihydrate; and 3) the artificially induced (higher) levels of related substances inhibit growth of new dihydrate crystals.
  • This model was applied to explain the improvement in dissolution assay with the age of the bulk lot, and conversely explain why the capsule dissolution assays trended downward as the bulk age decreased.
  • the amount of amorphous material in a given lot would decrease by decomposition or by relaxation to a lower energy state. Any residual dihydrate seed would be expected to continue to convert to the bulk form, as supported by thermodynamic and kinetic studies showing the dihydrate spontaneously dehydrates below a critical relative humidity.
  • a study of additional drying of cefaclor bulk in a laboratory rotary vacuum dryer (RVD) demonstrated that the performance of the bulk in the dissolution model tests improved with additional drying. Drying time and temperature were found to impact the NIR onset time. An increase in total related substances was also noted at elevated drying temperatures.
  • a study of additional drying of cefaclor bulk in a laboratory vacuum drying oven demonstrated a relationship between the water content of the bulk at the end of drying and the NIR onset time. The lower the ending water content, the longer the NIR onset time.
  • cefaclor related substances may influence the dissolution performance. It has been observed that the ⁇ 2-isomer, a known degradation product of cefaclor, influences the solubility versus time profiles of cefaclor in a manner which is consistent with inhibition of the recrystallization process (i.e., conversion of monohydrate to dihydrate) . A study was conducted to determine if degradation products of cefaclor might have an inhibitory effect on the rate of conversion of cefaclor to the dihydrate form. In the first study, a crystalline sample of the ⁇ 2-isomer (1) was used.
  • the ⁇ 2-isomer was added to a poorly dissolving lot of cefaclor at 0.5% concentration by weight.
  • the sample was mixed in the dry state. After addition of 1 ml of water to a 0.80 g sample, the X-ray diffraction pattern was collected at different time intervals. It was found that there was a minor inhibitory effect. The addition of the
  • ⁇ 2-isomer may have had a more significant effect if the material was mixed in a liquid rather than in a dry state.
  • Fraction 5 consists of two main peaks, the ⁇ 2- isomer of cefaclor (1) and cefaclor itself, along with a small amount of the front part of a "broad peak” region.
  • Fraction 6 also contains a significant amount of the front part of the "broad peak” region along with decarboxylated cefaclor (2) and smaller amounts of other degradation products of cefaclor which are unidentified.
  • the term "adding related substances" includes not only the physical addition of related substances but also addition by means of heating the material to generate the related substances.
  • the preferred means is by adding the related substances physically since one would have more control over the amounts added.
  • the pharmaceutical formulation has also been observed to exhibit faster capsule dissolution rates when the formulation mix is aged prior to filling into capsules. Although the mechanism of this aging phenomenon is not currently known, one can reasonably speculate that the effect of aging the formulation is the same as that observed in the aging of bulk cefaclor. Dihydrate seeds whether in the bulk or in the pharmaceutical mix would have a potential effect on the dissolution rates of cefaclor capsules. The lower the level of dihydrate seed, the less the effect on capsule dissolution rates. From a thermodynamic perspective, dihydrate seeds may be removed by slow equilibration (or aging) . Thus an additional short aging step, either at the bulk or at the mixing step (or even at the capsule stage) would allow time for the residual dihydrate seeds to convert to cefaclor bulk via the thermodynamic process.
  • the observation might be related to the hygroscopicity of cefaclor bulk. For example, there might be some redistribution of water between cefaclor and the excipients. Thus, the dissolution characteristics of the excipient(s) might contribute to the observed effects.
  • the process of mixing may be causing some shearing and grinding of the cefaclor crystals thus increasing the amount of amorphous material. Grinding is well known to increase the disorder and/or amorphous character of crystalline materials. The hold time following mixing of the formulation would allow time for the high-energy materials and/or amorphous cefaclor to relax.
  • minutes at 37°C includes the steps of (i) providing a cefaclor bulk form prepared by any of the processes described herein; (ii) mixing the cefaclor bulk form with a pharmaceutically acceptable carrier to form a mixture; and (iii) filling a capsule with the mixture.
  • Suitable pharmaceutically acceptable carriers include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, and the like.
  • the formulations may also include wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, sweeteners, perfuming agents, flavoring agents and combinations thereof.
  • Cefaclor dihydrate may be prepared from the anhydrate, monohydrate or solvate (e.g., the solvate described in Example 4 of U.S. Patent No. 5,608,055) using the general procedures described in Martinex, Heriberto, et al . , "Solid-state Chemistry and Crystal Structure of Cefaclor Dihydrate", Pharm. Res . 7(2), 147- 53 (1990) .
  • Cefaclor anhydrate, monohydrate or solvate is dissolved in 1M HC1 (pH approximately 1.4).
  • Activated charcoal is added to the solution and filtered.
  • the pH of the filtered solution is raised to about 3.6 to 4.5 by adding ammonium hydroxide.
  • the cefaclor dihydrate is then crystallized from the solution by cooling the slurry to about 0°C to 20°C.
  • Aqueous Dispersibili ty Test Approximately 100 mg of bulk cefaclor is placed on a glass slide. De-ionized water (approximately 6 drops) is added to the edge of the cefaclor. After five minutes of exposure to water, a glass slide cover slip is used to inspect the sample. A sample fails if the sample agglomerates. A sample passes if the wet-bulk cefaclor is flowable in nature.
  • NIR Dihydrate Conversion Test Approximately 1 to 2 grams of sample was spread in a thin layer on the bottom of an open aluminum weighing pan and placed in a constant humidity chamber, containing a saturated aqueous solution of K 2 HP0 4 , for at least two hours prior to analysis. Following equilibration in the humidity chamber, the sample was packed into a 2 mm x 6 mm, stainless steel sample cup until full (approximately 35 mg) , and 6 ⁇ L of water placed in the center of the sample. NIR data were collected using the NIR Systems model 5000 equipped with a fiber optic diffuse- reflectance probe, positioned over the sample cup.
  • Dissolution testing is continued with additional units through three stages unless the results conform at either the 1 st or 2 nd stage according to the following acceptance
  • S2 6 Average of 12units (S1+S2) is equal to or greater than Q, and no unit is less than Q-15%
  • S3 12 Average of 24 units (S1+S2+S3) is equal to or greater than Q, not more than 2 units are less than Q- 15%, and no unit is less than -25 ⁇
  • the quantity, Q is the % of dissolved active ingredient in the specification.
  • each individual unit must be at least 85% dissolved in 30 minutes to pass the testing. If any of the 6 units tested is less than 85% dissolved, the product fails level SI and you must go to S2.
  • the mean of the twelve units tested (first 6 from SI and 6 from S2) must be at least 80% dissolved and no unit may be less than 65% dissolved. If these criteria are not met, the product fails the level S2 specification and you must go to S3.
  • the mean of the 24 units tested (6 from SI + 6 from S2 + 12 from S3) must be at least 80% dissolved, no more than 2 units may be less than 65% dissolved, and none of the units may be less than 55% dissolved.
  • Examples 1 and 2 compare the results of monohydrate bulk materials generated by the old method (control) with the dehydration process and the dehydration/rehydration process for improving the dissolution rate.
  • Cefaclor dihydrate is dried in a fluidized bed at not more than 70°C (refers to product temperature) to a water content range of 3.0 to 6.5% water by Karl Fischer analysis. Bulk material produced using this method had an average NIR onset time of 1.2 minutes with an upper control limit of approximately 2.5 minutes.
  • Example 1 illustrates the effect on NIR onset time when a sample of cefaclor dihydrate is dried to a lower water content using the same procedures as described in the control above with longer drying times.
  • Table 2 summarizes the NIR onset times observed at the corresponding water contents of the resultant cefaclor monohydrate .
  • Example 2 illustrates the process for producing cefaclor bulk material that has been dehydrated and then rehydrated back to a water content between 3.0 and 6.5%.
  • Cefaclor dihydrate is dried in a fluidized bed at not more than 70°C (refers to product temperature) to a lower water content under two different drying conditions: Condition #1 - NMT 10 grains of moisture/pound of dry air (full desiccation) ; and Condition #2 - NMT 40 grains of moisture/pound of dry air.
  • the resultant product is then rehumidified with humidified air to a water content between 3.0 to 6.5%.
  • Tables 3 and 4 summarize the dissolution rates of capsules made from bulk materials produced by the dehydration/rehydration process described above.
  • Tables 3 and 4 show that rehydration of the bulk material that was produced under either condition 1 or 2 had little effect on the dissolution rate of the capsules. No failures were observed when the bulk material was dried to ⁇ 2.0% under full desiccation conditions and then rehydrated. Some failures were noted when the bulk material was dried under condition 2 (40 grains of moisture/pound of dry air) . It is very difficult to reach water contents less than 2% under this drying condition. The lowest water content observed for samples 2-2a through 2-2c was 2.6%, 2.7% and 2.4% respectively. Although acceptable material may be produced at water contents less than 3.0%, preferably the water content is reduced to less than 2.0%.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé permettant l'élaboration de cristaux en vrac de céfaclor présentant une vitesse de dissolution dans une capsule d'au moins 80% en 30 minutes. L'un des modes d'élaboration consiste à réduire la teneur en eau de céfaclor dihydrate ou de matière en vrac contenant du céfaclor dihydrate de façon à obtenir une forme de céfaclor dont la teneur en eau n'excède par 2%. En cas de teneur en eau inférieure, on peut réhydrater le céfaclor jusqu'à 3,0 à 6,5% sans que cela soit au détriment de la vitesse de dissolution. Un autre procédé consiste à ajouter au moins 0,05% de substances apparentées au céfaclor de façon à bloquer le passage de la forme monohydrate à la forme dihydrate.
EP99927538A 1999-05-14 1999-06-15 Elaboration d'un produit pharmaceutique en vrac uniformement dissout Withdrawn EP1180022A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13421599P 1999-05-14 1999-05-14
US134215P 1999-05-14
PCT/US1999/013481 WO2000069417A1 (fr) 1999-05-14 1999-06-15 Elaboration d'un produit pharmaceutique en vrac uniformement dissout

Publications (2)

Publication Number Publication Date
EP1180022A1 true EP1180022A1 (fr) 2002-02-20
EP1180022A4 EP1180022A4 (fr) 2004-01-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99927538A Withdrawn EP1180022A4 (fr) 1999-05-14 1999-06-15 Elaboration d'un produit pharmaceutique en vrac uniformement dissout

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EP (1) EP1180022A4 (fr)
AU (1) AU4441899A (fr)
WO (1) WO2000069417A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465615B1 (en) * 2001-09-10 2002-10-15 Astrazeneca Ab Monohydrate lisinopril
US6468976B1 (en) * 2001-09-10 2002-10-22 Astrazeneca Ab Monohydrate lisinopril

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713247A (en) * 1983-06-15 1987-12-15 Shionogi & Co., Ltd. Long-acting formulation of cefaclor
US4968508A (en) * 1987-02-27 1990-11-06 Eli Lilly And Company Sustained release matrix
US5516531A (en) * 1987-01-29 1996-05-14 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
US5837292A (en) * 1996-07-03 1998-11-17 Yamanouchi Europe B.V. Granulate for the preparation of fast-disintegrating and fast-dissolving compositions containing a high amount of drug

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1251999B (it) * 1991-11-11 1995-05-27 Opos Biochimica Srl Forma cristallina di un antibiotico cefalosporinico

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713247A (en) * 1983-06-15 1987-12-15 Shionogi & Co., Ltd. Long-acting formulation of cefaclor
US5516531A (en) * 1987-01-29 1996-05-14 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
US4968508A (en) * 1987-02-27 1990-11-06 Eli Lilly And Company Sustained release matrix
US5837292A (en) * 1996-07-03 1998-11-17 Yamanouchi Europe B.V. Granulate for the preparation of fast-disintegrating and fast-dissolving compositions containing a high amount of drug

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHOW ALBERT H L ET AL: "Parameters affecting in-liquid drying microencapsulation and release rate of cefaclor." INTERNATIONAL JOURNAL OF PHARMACEUTICS (AMSTERDAM), vol. 172, no. 1-2, 15 October 1998 (1998-10-15), pages 113-125, XP001147521 ISSN: 0378-5173 *
See also references of WO0069417A1 *

Also Published As

Publication number Publication date
EP1180022A4 (fr) 2004-01-07
WO2000069417A1 (fr) 2000-11-23
AU4441899A (en) 2000-12-05

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