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WO1999030688A1 - Procedes de lyophilisation de solutions - Google Patents

Procedes de lyophilisation de solutions Download PDF

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Publication number
WO1999030688A1
WO1999030688A1 PCT/GB1998/003747 GB9803747W WO9930688A1 WO 1999030688 A1 WO1999030688 A1 WO 1999030688A1 GB 9803747 W GB9803747 W GB 9803747W WO 9930688 A1 WO9930688 A1 WO 9930688A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
sublimation
temperature
excipient
drying
Prior art date
Application number
PCT/GB1998/003747
Other languages
English (en)
Inventor
Anthony Auffret
Original Assignee
Anthony Auffret
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 Anthony Auffret filed Critical Anthony Auffret
Priority to AU15701/99A priority Critical patent/AU1570199A/en
Publication of WO1999030688A1 publication Critical patent/WO1999030688A1/fr

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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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates to methods of lyophilizing or freeze-drying solutions and to products obtainable by such methods.
  • the present invention relates to methods of lyophilizing solutions by including substances that enhance the rate of solvent sublimation and/or that obviate the need for subsequent drying steps.
  • Freeze-drying has established itself as the standard method for the stabilisation of many drug substances in the solid state. Compared to other drying processes, the technology is capital-, labour- and energy-intensive. Its optimisation depends on a complex interplay of several formulation and processing parameters; these have been highlighted in several recent product and process development studies (1, 2). Particular attention is currently being paid to the mechanisms and control of deleterious physical and/ or chemical changes that might occur during freeze concentration of an initially dilute solution, during the ice sublimation phase, and thereafter. In the extreme, such changes render a dried product slow to rehydrate or even lead to partial or total inactivation, denaturation or modification. Some investigations have concentrated on the use of suitable additives, specifically to enable process cycle times to be reduced, with resulting economies.
  • TBA tertiary butanol
  • TBA TBA
  • the specific effe ⁇ of TBA, on the system, is said to be related solely to its ability to modify the ice crystal habit. This leads to the growth of needle-shaped crystals, producing a significant increase in the specific surface area available for sublimation, and a concomitant decrease in the resistance of the dried cake to mass transfer. This enables the drying temperature to be raised and the sublimation cycle to be substantially shortened.
  • TBA does indeed affect T ' of freeze-concentrated sucrose solutions, without measurably affe ⁇ ing the water content of the freeze concentrate, thus implying that at least some TBA is retained in the concentrated, amorphous phase in the form of a solid solution.
  • residual TBA may be considered disadvantageous for many pharmaceutical, diagnostic or food products; for example parenteral produ ⁇ s intended for human inje ⁇ ion.
  • the eute ⁇ ic temperature T c must be established, i.e. the lowest temperature at which any of the precipitated components (including ice) melt and re-dissolve back into the produ ⁇ .
  • freeze-concentrated produ ⁇ remains homogenous, freezing slows down and eventually ceases, in real time.
  • the temperature at which the degree of freeze-concentration reaches its maximum value is referred to as the glass temperature T ' of the freeze-concentrated produ ⁇ , which then still contains
  • T ' and T " A rigorous differentiation is made between two apparent thermal transitions, called T ' and T ".
  • T g " The lower temperature T g " is associated with a marked viscosity change (a glass is defined as a solution with a viscosity of 10 14 Pa.s). Immediately above this temperature, however, the viscosity is still sufficiently high to severely inhibit diffusion and viscous flow.
  • T ' the higher temperature transition, is the point at which the viscosity is reduced for mechanical flow (collapse) to occur on this time scale of observation.
  • T ' the higher temperature transition, is the point at which the viscosity is reduced for mechanical flow (collapse) to occur on this time scale of observation.
  • T ' the higher temperature transition
  • the dried produ ⁇ must have a glass temperature in excess of the storage temperature.
  • T g of the dried produ ⁇ depends on formulation details and the residual moisture content (W . Knowledge of these quantities is particularly important for the design of accelerated stability tests and for predi ⁇ ions of produ ⁇ shelf life.
  • the process efficiency i.e. ice sublimation and secondary drying rates and the quality of the dried produ ⁇ are determined by several fa ⁇ ors, among them: a) Volume of water to be removed. b) Total solids content and chemical composition of the produ ⁇ . c) Liquid fill depth (i.e. container geometry). d) Temperature difference between produ ⁇ and condenser. e) Chamber pressure f) Efficiency of the freeze dryer.
  • DSC Differential scanning calorimetry
  • samples were cooled at 0.3 °C/minute and warmed at 5 °C/min. In some cases, to aid throughput, samples were cooled to -10 or -15 °C at5 °C/min prior to the 0.3 °/min slow cooling protocol. In all cases freezing (which must precede eute ⁇ ic crystallisation) occurred during the slow cooling regime.
  • the moisture content of the sample is the difference between the moisture content of the sample solution and of the blank vials.
  • Freeze-drying cycles were developed using "best pra ⁇ ice” as outlined in reference (3). All cycles were optimised for freezing behaviour, solids content, fill depth and container geometry.
  • Eletriptan and Sildenafil Freezing behaviour of Eletriptan and Sildenafil 8A Eletriptan 8.B Sildenafil 9. Freezing behaviour of formulated Eletriptan and Sildenafil 9.A Eletriptan / PVP formulations 9.A.1 Ammonium bicarbonate 9A.2 Ammonium formate 9.B.3 No salt; Eletriptan 5 mg/ml in 5% PVP 9.B Sildenafil / PVP formulations
  • the Perkin-Elmer DSC-2 instrument used in this work was fitted with Auto-scanning and subambient temperature accessories. Sample masses used were of the order of 15 mg.
  • the DARES data colle ⁇ ion and handling system was used for recording and processing DSC power-time curves. This system enables the normal sensitivity of the instrument to be increased by three orders of magnitude (Hatley et al., Thermochim. A ⁇ a 156, 247- 257(1989)).
  • Test solutions were cooled to 210-220K, and recording of DSC traces was started at 220-230K. The melting points of ice (273.2K) and indium (429.8K) were used for temperature calibration. Scanning rates for cooling and heating were 5 K/min, unless otherwise stated.
  • a standard DSC-7 instrument was used for a limited number of experiments.
  • T ' is independent of initial concentration.
  • the solubility of la ⁇ ose in water at room temperature is less than 25 g/100 ml. - lo -
  • a non crystallisable excipient to a salt solution would be expe ⁇ ed to inhibit eute ⁇ ic solidification, especially at higher excipien : salt ratio's.
  • a solution of ammonium bicarbonate has the following % by weight of solute.
  • AmForm for ammonium formate (formic acid, ammonium salt).
  • references below to crystallisation refer only to the salt component.
  • the excipient forms a freeze-concentrated glass and T ' may be depressed by the inclusion of some residual salt.
  • the recorded glass temperatures for the 0.1 M and 0.2 M solutions are consistent with glass temperatures below the recorded range for formulations containing greater amounts of the acetate salt.
  • the glass temperature of the 0.2 M ammonium acetate formulation is consistent with a depression of T Tin' below the recorded range when the salt concentration is increased.
  • the value of ⁇ Cp, 0.137 J/g °C allowed a reliable assignment of the transition.
  • eute ⁇ ic crystallisation of some salt during cooling of the 0.1 M acetate formulation see Fig. A6. Unusually, however, there seems to be no crystallisation from formulations containing greater amounts of the salt (see also 5% la ⁇ ose / 0.1 M ammonium formate, below).
  • the time course data points were not taken at regular intervals, typically overnight steps are longer.
  • the plotted time courses of sublimation are extrapolated from the available data with this limitation.
  • the 1 M ammonium bicarbonate solution dries more quickly than any other, but this may simply refle ⁇ the (lowest) solids content.
  • the 0.8 and 0.6 M salt with sucrose are similar to sucrose alone.
  • the 0.2 and 0.4 M salt additions accelerate drying compared to sucrose alone.
  • the DSC analysis would predi ⁇ that only the 0.8 and 0.6 M salt with sucrose contain a volatile eute ⁇ ic solid.
  • the la ⁇ ose / Ambic formulations show the same features as the sucrose mixtures.
  • the formulations expe ⁇ ed to contain volatile eute ⁇ ic solids, dry more slowly than la ⁇ ose alone.
  • the 0.2 and 0.4 M compositions show an enhancement of sublimation rate, compared to la ⁇ ose alone, despite having an increase solids content.
  • this data set includes an additional formulation containing 0.1 M ammonium acetate in 5% sucrose.
  • the photograph shows three vials from the 5% sucrose / Ambic series, 7a, 7b and 7c after primary drying for 51 hours.
  • the compositions are 7a - 5% sucrose
  • This 0.1 M result although showing a higher sublimation rate than sucrose alone, had a lower rate than the 0.2 and 0.4 M homologues.
  • the principal aim of this proje ⁇ is not to deueiop faster drying cydes, but to facilitate rapid rehydration. Comparative drying rates are intended as a guide to changes that might facilitate dissolution.
  • sucrose/acetate and PW/formate The highest sublimation rates are shown by sucrose/formate and sucrose/acetate.
  • the drying rate in this case increases as (T-T g ') decreases (where T is the drying temperature).
  • the drying rates are broadly similar for these mixtures.
  • the rate of ice sublimation is a fun ⁇ ion of temperature. 2. For a given salt additive, at a fixed drying temperature, there may be an inverse relationship between sublimation rate and (T-T g '). 3. Residual salt left in the produ ⁇ may be undesirable.
  • the temperature effe ⁇ alone would increase the rate of ice sublimation by approximately 150%.
  • the higher T ' temperature will also be of value, when formulating with drug substances. Any plasticising a ⁇ ive materials would depress T ' and with the formate salt may therefore lead to undesirable but necessary long cycle times.
  • the sample was subje ⁇ ed to a set of heating and cooling cycles, with the obje ⁇ of discriminating between reversible (e.g. glass transitions) and irreversible (e.g. melting) changes.
  • the regime was (rates are 5 °C unless otherwise given)
  • the lowest T ' value of -32 °C can be used to determine satisfa ⁇ ory cycle parameters, although the composition of the produ ⁇ may be somewhat variable.
  • Formulations were prepared by dilution of a stock solution of Sildenafil, 10 mg/ml, in 100 mM HC1 and are (final concentration) Sildenafil 5 mg/ml in 50 mM HO, 5% PW. WO 99/30688 - . _ ⁇ . PCT/GB98/03747
  • Freeze drying experiments were carried out using 1 ml samples in 1.6 cm i.d. vials. The following formulations were studied;
  • Annealing was carried out by cooling to below T ' and warming to the temperature shown. Primary drying was carried out at a produ ⁇ temperature of -46 °C. The relative sublimation rates are shown overpage.
  • Vials were initially stored for 24 h at 4 °C. No further collapse was evident.
  • DSC power-time curves can be found in Appendix A, figures A.20 to A.25.
  • Fig 15 illustrates the typical features which are summarised below.
  • DSC Power-time curves may be found in Appendix A, figures A.26 to A.34.
  • the glass temperatures of the primary dried samples especially the Sildenafil / PW formulation, suggest that it may be possible to produce ambient temperature stable produ ⁇ s either with limited secondary drying or simply by increasing the PW content.
  • DSC Power-time curves may be found in Appendix A, figures A.34 and A.35.
  • the sample analysed had not collapsed during storage, and surprisingly two transitions are evident.
  • the Eletriptan / PW/ ammonium formate produ ⁇ has the chara ⁇ eristics of a stable rapidly dissolving dosage form that is mechanically stable. Although the handling properties are not chara ⁇ erised, the analogous Sildenafil formulation is similar. Such produ ⁇ s could be freeze-dried in a blister pack (the use of plastic containers does not cause significant changes in freeze-drying behaviour) and could be "dispensed" dire ⁇ ly onto the tongue of a neo-natal, paediatric or geriatric patient. Produ ⁇ collapse is sufficiently rapid to ensure that the medication cannot be unilaterally reje ⁇ ed. The ratios of excipient, accelerant and a ⁇ ive material have not been optimised and thus the prognosis for improvement and extension of these properties to other drug substances and formulations is good.
  • A.1 Enlarged power-time curve for the slow cooling of 5% PW /
  • Eletriptan.HBr solution54 A.17 Enlarged power-time curve for the warming of 5% PW /

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention porte sur un procédé de lyophilisation d'une solution, procédé qui consiste à congeler la solution à une température égale ou inférieure à sa température eutectique la plus basse ou à sa température de transition du verre, et, dans une étape de séchage, à retirer au moins une partie du solvant par sublimation. Ce procédé se caractérise en ce que la solution contient un excipient catalyseur de façon à accroître la vitesse de sublimation du solvant.
PCT/GB1998/003747 1997-12-13 1998-12-14 Procedes de lyophilisation de solutions WO1999030688A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15701/99A AU1570199A (en) 1997-12-13 1998-12-14 Methods of lyophilizing solutions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9726343.8 1997-12-13
GBGB9726343.8A GB9726343D0 (en) 1997-12-13 1997-12-13 The use of excipients to accelerate freeze-drying

Publications (1)

Publication Number Publication Date
WO1999030688A1 true WO1999030688A1 (fr) 1999-06-24

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Application Number Title Priority Date Filing Date
PCT/GB1998/003747 WO1999030688A1 (fr) 1997-12-13 1998-12-14 Procedes de lyophilisation de solutions

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AU (1) AU1570199A (fr)
GB (1) GB9726343D0 (fr)
WO (1) WO1999030688A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
WO2000007597A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Systeme de traitement transmuqueux pour l'utilisation de sildenafil
WO2000007596A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Formulation pharmaceutique soluble dans l'eau pour l'utilisation de sildenafil
WO2005102274A3 (fr) * 2004-04-22 2006-03-30 Pfizer Prod Inc Procede de stabilisation de sel de sodium de cefovecine desordonne
FR2881139A1 (fr) * 2005-01-26 2006-07-28 Agronomique Inst Nat Rech Composition pour la lyophilisation de proteines
WO2008137134A3 (fr) * 2007-05-01 2009-02-05 Plus Chemicals Bv Bromhydrate d'élétriptan amorphe et son procédé de préparation, et autres formes de bromhydrate d'élétriptan
US8158152B2 (en) 2005-11-18 2012-04-17 Scidose Llc Lyophilization process and products obtained thereby
CN109984321A (zh) * 2019-03-27 2019-07-09 齐鲁工业大学 一种高粘度山药粉的低能耗制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981676A (en) * 1970-03-03 1976-09-21 L'oreal Lyophilized dyes and the use thereof to color keratinic fibers
JPH03297384A (ja) * 1990-04-13 1991-12-27 Taunzu:Kk 尿素アミドリアーゼの安定化組成物
WO1993014191A1 (fr) * 1992-01-21 1993-07-22 Cryopharm Corporation Procede de congelation de cellules et de matieres analogues a des cellules
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
EP0656211A1 (fr) * 1993-11-09 1995-06-07 American Cyanamid Company Composition stabilisée et lyophilisée de thiotépa
WO1996033744A2 (fr) * 1995-04-28 1996-10-31 Inhale Therapeutic Systems Compositions en phase vitreuse, stabilisees par un sucre
WO1997036577A1 (fr) * 1996-04-02 1997-10-09 Pharmos Corporation Compositions lipidiques solides de composes lipophiles pour ameliorer la biodisponibilite orale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981676A (en) * 1970-03-03 1976-09-21 L'oreal Lyophilized dyes and the use thereof to color keratinic fibers
JPH03297384A (ja) * 1990-04-13 1991-12-27 Taunzu:Kk 尿素アミドリアーゼの安定化組成物
WO1993014191A1 (fr) * 1992-01-21 1993-07-22 Cryopharm Corporation Procede de congelation de cellules et de matieres analogues a des cellules
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
EP0656211A1 (fr) * 1993-11-09 1995-06-07 American Cyanamid Company Composition stabilisée et lyophilisée de thiotépa
WO1996033744A2 (fr) * 1995-04-28 1996-10-31 Inhale Therapeutic Systems Compositions en phase vitreuse, stabilisees par un sucre
WO1997036577A1 (fr) * 1996-04-02 1997-10-09 Pharmos Corporation Compositions lipidiques solides de composes lipophiles pour ameliorer la biodisponibilite orale

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9207, Derwent World Patents Index; Class D16, AN 92-053611 *
DELUCA P. ET AL: "Acceleration of freeze drying cycles of aqueous solutions of lactose and sucrose with tertiary butyl alcohol", CONGR. INT. TECHNOL. PHARM., vol. 1, no. 5, 1989, pages 439 - 447, XP002103017 *
KASRAIAN K. ET AL: "The effect of tertiary butyl alcohol on the resistance of the dry product layer during primary drying", PHARM. RES., vol. 12, no. 4, April 1995 (1995-04-01), pages 491 - 495, XP002103015 *
KASRAIAN K. ET AL: "Thermal analysis of the tertiary butyl alcohol water system and its implication on freeze drying", PHARM. RES., vol. 12, no. 4, April 1995 (1995-04-01), pages 485 - 486, XP002103016 *
OESTERLE J. ET AL: "The influence of tertiary butyl alcohol and volatile salts on the sublimation of ice from frozen sucrose solutions: implications for freeze drying", PHARM. DEV. AND TECHNOL., vol. 3, no. 2, 1998, pages 175 - 183, XP002103023 *
OVERCASHIER D E ET AL: "PREPARATION OF EXCIPIENT-FREE RECOMBINANT HUMAN TISSUE-TYPE PLASMINOGEN ACTIVATOR BY LYOPHILIZATION FROM AMMONIUM BICARBONATE SOLUTION: AN INVESTIGATION OF THE TWO-STAGE SUBLIMATION PHENOMENON", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 86, no. 4, 1 April 1997 (1997-04-01), pages 455 - 459, XP000683466 *
PATENT ABSTRACTS OF JAPAN vol. 016, no. 140 (C - 0926) 8 April 1992 (1992-04-08) *
SHAMBLIN S. ET AL: "The effects of co lyophilized polymeric additives on the glass transition temperature and crystallization of amorphous sucrose", J. THERM. ANAL., vol. 47, no. 5, 1996, pages 1567 - 1579, XP002103018 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
US6200591B1 (en) 1998-06-25 2001-03-13 Anwar A. Hussain Method of administration of sildenafil to produce instantaneous response for the treatment of erectile dysfunction
WO2000007597A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Systeme de traitement transmuqueux pour l'utilisation de sildenafil
WO2000007596A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Formulation pharmaceutique soluble dans l'eau pour l'utilisation de sildenafil
WO2005102274A3 (fr) * 2004-04-22 2006-03-30 Pfizer Prod Inc Procede de stabilisation de sel de sodium de cefovecine desordonne
FR2881139A1 (fr) * 2005-01-26 2006-07-28 Agronomique Inst Nat Rech Composition pour la lyophilisation de proteines
WO2006079722A3 (fr) * 2005-01-26 2006-10-19 Agronomique Inst Nat Rech Compositions pour la lyophilisation de proteines
US8158152B2 (en) 2005-11-18 2012-04-17 Scidose Llc Lyophilization process and products obtained thereby
WO2008137134A3 (fr) * 2007-05-01 2009-02-05 Plus Chemicals Bv Bromhydrate d'élétriptan amorphe et son procédé de préparation, et autres formes de bromhydrate d'élétriptan
CN109984321A (zh) * 2019-03-27 2019-07-09 齐鲁工业大学 一种高粘度山药粉的低能耗制备方法
CN109984321B (zh) * 2019-03-27 2022-08-16 齐鲁工业大学 一种高粘度山药粉的低能耗制备方法

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Publication number Publication date
AU1570199A (en) 1999-07-05
GB9726343D0 (en) 1998-02-11

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