U.S. patent application number 10/470885 was filed with the patent office on 2004-07-29 for malic acid addition salts of terbinafine.
Invention is credited to Giron, Danielle, Hirsch, Stefan, Reber, Jean-Louis.
Application Number | 20040147603 10/470885 |
Document ID | / |
Family ID | 9908301 |
Filed Date | 2004-07-29 |
United States Patent
Application |
20040147603 |
Kind Code |
A1 |
Giron, Danielle ; et
al. |
July 29, 2004 |
Malic acid addition salts of terbinafine
Abstract
The invention concerns salts of the compound of formula I 1 with
malic acid, their preparation, corresponding pharmaceutical
compositions and their use as antimycotics.
Inventors: |
Giron, Danielle; (Mulhouse,
FR) ; Reber, Jean-Louis; (Kembs, FR) ; Hirsch,
Stefan; (Lorrach, DE) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
9908301 |
Appl. No.: |
10/470885 |
Filed: |
February 18, 2004 |
PCT Filed: |
February 6, 2002 |
PCT NO: |
PCT/EP02/01249 |
Current U.S.
Class: |
514/554 ;
514/649; 562/579 |
Current CPC
Class: |
A61P 41/00 20180101;
C07C 211/30 20130101; A61P 31/10 20180101; A61P 27/16 20180101;
A61K 31/137 20130101 |
Class at
Publication: |
514/554 ;
514/649; 562/579 |
International
Class: |
A61K 031/205 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 7, 2001 |
GB |
0103046.9 |
Claims
1. A salt of the compound of formula I 3with malic acid.
2. A compound according to claim 1 in the form of the
L-(-)-hydrogen malate.
3. A process for the preparation of a compound according to claim 1
which comprises reacting the compound of formula I in free base
form with an appropriate malic acid form and recovering from the
reaction mixture the resultant salt.
4. A pharmaceutical composition comprising a compound according to
claim 1 together with at least one pharmaceutically acceptable
carrier or diluent.
5. A pharmaceutical composition comprising the compound of formula
I in free base form or pharmaceutically acceptable salt form other
than a malic acid addition salt form, whenever prepared from a
compound according to claim 1.
6. A compound according to claim 1 for use as a pharmaceutical.
7. A compound according to claim 1 for use in the preparation of a
medicament.
8. The compound of formula I in free base form or a salt form other
than a malic acid addition salt form, whenever prepared from a
compound according to claim 1.
9. The use of a compound according to claim 1 in the preparation of
a medicament for the treatment of diseases susceptible of therapy
with the compound of formula I in free base form or salt form.
10. A method for the prophylactic or curative treatment of fungal
diseases such as fungal sinusitis infection or onychomycosis,
comprising administration of a therapeutically effective amount of
a compound according to claim 1 to a subject in need of such
treatment.
Description
[0001] The invention relates to acid addition salts of allylaniine
antirnycotics.
[0002] It concerns salts of the compound of formula I 2
[0003] with malic acid, i.e.
(E)-N-methyl-6,6-dimethyl-N-(1-naphthylnethyl-
)hept-2-en-4-inyl-1-amine in malic acid addition salt form,
hereinafter briefly named "the compounds of the invention".
[0004] The compounds of the invention are novel and improved
pharmaceutical salts of the known compound of formula I.
[0005] A compound of the invention is in racemic or enantiomeric
form. It is in malate or hydrogen malate, preferably in hydrogen
malate, acid addition salt form. The malic acid moiety preferably
is in racemic DL-(.+-.)- or L-(-)-enantiomeric, especially in
L-(-)-enantiomeric form. Particularly preferred are thus the
DL-(.+-.)- and the L-(-)-, especially the L-(-)-hydrogen
malate.
[0006] The compounds of the invention exhibit polymorphism The
invention includes the compounds of the invention in any
polymorphic form, e.g. form A or form B of the L-(-)-hydrogen
malate as described hereunder.
[0007] The invention also includes a process for the preparation of
a compound of the invention which comprises reacting the compound
of formula I in free base form with an appropriate malic acid form
and recovering from the reaction mixture the resultant salt.
[0008] The process of the invention may be effected in conventional
manner, e.g. by reaction in an appropriate inert solvent such as
isopropanol, acetic acid ethyl ester, isopropyl acetate,
cyclopentanone, n-butanol or ethyl formate.
[0009] The compound of formula I in hydrochloric acid addition salt
form and its use as an antimycotics e.g. in the treatment of
mycosis caused by dermatophyte infection, is known i.a. from EP
24687 and its equivalents. It is available in free base or
hydrochloric acid addition salt form under the trademark
Lamisil.sup.R, with the generic name terbinafine. Two further salt
forms have also been mentioned in the literature, e.g. in EP
515310A1, the lactate and the ascorbate, in relation with
pharmaceutical compositions for topical application on skin.
[0010] Terbinafine is an orally and topically effective anti-fungal
agent. It is effective in a wide range of fungal diseases,
including i.a. fungal sinusitis infection and onychomycosis. It is
particularly useful against dermatophytes, contagious fungi that
invade dead tissues of the skin or its appendages such as stratum
corneum, nails, and hair. Such a nail fungus makes its home in the
nail bed, shielded by the hard outer nail. Thus once infection is
established under the nail, the nail itself provides the fungus
with a protected environment that allows it to grow. The effects of
these fungi on the nails may be unsightly, they seriously
complicate foot-care, have a deleterious impact on the patient's
overall quality of life and well-being and impair the patient's
ability to work. If left untreated, the fungi can deform toenails
permanently and lead to pain on walking. Additionally the fungi can
lead to fissures in the skin encouraging bacterial infections.
Serious complications as a result of these infections may occur in
people suffering from diabetes such as diabetic foot syndrome
including primary disease-related complications, e.g. gangrene
that, ultimately, can be life-threatening or require amputation.
Other high-risk patient sub-groups include patients infected with
human immunodeficiency virus (HIV), patients with acquired
immunodeficiency syndrome (AIDS), and patients with other types of
immunosuppression (e.g. transplant recipients and patients on long
term corticosteroid therapy). There is an increased prevalence of
onychomycosis in the elderly (up to 30% by age 60). Microsporum,
Trichophyton such as Trichophyton rubrum or Trichophyton
mentagrophytes, and Epidermophyton such as Epidermophyton floccosum
are those fungi commonly involved Across medical disciplines,
onychomycosis is well recognized as being arduous both to diagnose
and to manage, particularly in the aged.
[0011] Terbinafine is also useful to treat toenail and fingernail
onychomycosis (e.g. Tinea unguium) due to dermatophytes. Indeed
terbinafine has opened up treatment for Tinea unguium caused by
Trichophyton. For example it has been stated that treatment of
toenails should be discouraged with the previously used standard,
griseofulvin, because 1 to 2 years treatment is required,
recurrence is usual and complete cure unlikely.
[0012] For the oral use in onychomycosis, terbinafine hydrochloride
is normally administered as an immediate release tablet form
containing 250 mg terbinafine once daily. Such a tablet, sold under
the trademark Lamisil.sup.R releases terbinafine to the extent of
80% over a 30 minute period as measured by standard in vitro
dissolution studies, e.g. at pH 3 using the paddle method.
Terbinafine treatment over 12 weeks is required. The progress of
its clinical effectiveness is seen with growth of the healthy nail,
pushing out and replacing the diseased unsightly nail containing
debris and dead fungus. About 10 months is needed for a totally new
toenail to form.
[0013] Although terbinafine is generally regarded to be as safe as
any prescription drug, adverse events associated with its use have
been reported. There have been a number of adverse events recorded,
e.g. headaches, gastrointestinal symptoms (including diarrhea,
dyspepsia, abdominal pain, nausea and flatulence), liver test
abnormalities, e.g. enzyme abnormalities, dermatological symptoms
such as pruritis, urticaria and rashes, and taste disturbances,
e.g. loss of taste. These adverse events are in general mild and
transient. Further adverse events include symptomatic idiosyncratic
hepatobiliary dysfunction (e.g. cholestatic hepatitis), severe skin
reactions such as Stevens-Johnson syndrome, neutropenia, and
thrombocytopenia. Yet further adverse events may include visual
disturbances such as changes in the ocular lens and retina, as well
as allergic reactions including anaphylaxis, fatigue, vomiting,
arthralgia, myalgia and hair loss. Terbinafine is a potent
inhibitor of CYP2D6 and may cause clinically significant
interactions when co-administered with substrates of this isoform,
such as nortriptyline, desipramnine, perphenazine, metoprolol
encainide and propafenone. Hereinafter any and all these events are
referred to briefly as Adverse Events.
[0014] Pharmacokinetic and biopharmaceutical properties of
terbinafine hydrochloride are known. Thus it is well absorbed. Peak
drug plasma concentrations (hereinafter C.sub.max) of about 1.3
.mu.g/ml (with about a 20% variation, e.g. 0.9 to 1.6 .mu.g/ml)
appear in human subjects within 1 to 2 hours after administration
of a single 250 mg terbinafine dose. The area under the curve over
24 hours (hereinafter AUC) is about 4.76 .mu.g.hour/ml. The
increase in AUC is 42% when terbinafine is administered with a
fat-rich meal. In patients with renal impairment (e.g. creatinine
clearance.gtoreq.50 ml/min) or hepatic cirrhosis, the clearance of
terbinafine is reduced by approximately 50%. In the steady state,
e.g. when the trough and peaks are constant after several days
dosing, in comparison to the single dose, C.sub.max is 25% higher
and the AUC increases by a factor of 2.5. This is consistent with
an effective half-life for terbinafine of about 36 hours.
[0015] Pharmacokinetic and absorption properties have been
disclosed e.g. in J. Faergemann et al., Acta Derm. Venereol.
(Stockh.) 77 (1997) 74-76. The site of absorption of terbinafine
is, however, not known and there is no clinically proven
correlation of effect with pharmacokinetic profile, so there is no
rational starting point for developing pharmaceutical forms
containing terbinafine with improved therapeutic effects.
[0016] Despite the very major contribution which terbinafine has
made, the reported occurrence of undesirable Adverse Events has
been an impediment to its wider oral use or application. The
particular difficulties encountered in relation to oral dosing with
terbinafine hydrochloride have inevitably led to restrictions in
the use of terbinafine therapy for the treatment of relatively less
severe or endangering disease conditions, e.g. Tinea pedis.
[0017] It has now been found that, unexpectedly, salts of the
compound of formula I with malic acid possess particularly
beneficial pharmacokinetic properties, and have further been found
to possess a unique combination of favourable formulation
properties which make them particularly suitable for the
preparation of pharmaceutical compositions of terbinafine adapted
for systemic and topical administration.
[0018] Thus the variability of pharmacokinetic parameters is
considerably less when a malate salt of the compound of formula I
is employed systemically than with known salts or the free base,
e.g. the hydrochloride.
[0019] This appears i.a. from a pharmacokinetic study in animals
involving 7 Beagle dogs weighing about 10 kg, aged about 5 years,
upon oral administration of capsules prepared by mixing active
terbinafine salt substance [hydrochloride or L-(-)-hydrogen malate;
62.5 mg base equivalent per capsule] with lactose in a ratio of 1:1
w/w and filling into appropriate hard gelatine capsules (particle
size distribution similar for both salts).
[0020] The inter-animal variability in plasma exposure of
terbinafine (as expressed by the coefficient of variation
[hereinafter CV] of the area-under-the-curve [AUC] has been found
to be distinctly reduced when the L-(-)-hydrogen malate salt of
terbinafine is administered, namely 30%, as compared with 39% with
the hydrochloride. The mean AUC values obtained thereby were,
respectively, 392 and 348 ng.hour/ml, showing even a slight
increase in absolute plasma exposure with the hydrogen malate
salt.
[0021] The mean C.sub.max values obtained thereby are 134 and 146
ng/ml for the L-(-)-hydrogen malate and the hydrochloride,
respectively, with corresponding CV values 26% and 47%,
respectively, a further indication of reduced variability of
pharmacokinetic parameters when a malate salt is used.
[0022] It can be expected therefrom that in human subjects, a
similarly reduced variability of pharmacokinetic parameters is
obtained, and thus even more stable efficacy of treatment with
terbinafine in antimycotic indications may be envisaged, even at
very high dosages, in particular upon oral administration, e.g. in
the oral treatment of onychomycosis.
[0023] Further, the compounds of the invention may also be employed
topically, e.g. on the nail, as appears for example from the
following in vitro penetration/permeation assay:
[0024] Human cadaveric toe nails are used in a Franz cell (FIG. 1)
modified to accept cadaveric human toenails by having a pair of
flexible rings made of a silicone elastomer (PDMS) having good
sealant properties to adequately mount hard nails, using liquid
scintillation counting (LSC) (picogram limit of detection) to
measure the increase in radioactivity in the acceptor compartment.
Each measurement is effected in triplicate. 90 randomly selected
nails are exposed for 72 hours to a solution of 100 .mu.l of
.sup.14C-labelled terbinafine hydrochloride or terbinafine
L-(-)-hydrogen malate (form A) solution [25 .mu.Bq/ml; 1% active
product; 5% 1,2-propylene glycol; 2%
Cetomacrogol-1000.sup.R(polyoxyethylene-glyco-
l-1000-monoacetylether); 25% ethanol 94%; 67% distilled water]
(w/w). Each area of the nail exposed to the formulation has a 9 mm
diameter (about 64 mm.sup.2). Exposure is effected under occlusive
(chamber closed to air) and non-occlusive (chamber open to air)
conditions.
[0025] The radiolabelled product is detectable in the buffer-filled
receptor chamber from about 8 hours of incubation. Its
concentration in the receptor chamber as measured by LSC increases
with incubation time and concentration of applied formulation. A
total of 24 penetration chambers are used in parallel. Each
formulation is measured in triplicate.
[0026] The result is as appears from FIG. 2: under both occlusive
(black dots) and non-occlusive (black squares) conditions, at 72
hours substantial permeation is observed (about 63 ng and 41 ng,
respectively).
[0027] Further, it has been found that the compounds of the
invention surprisingly possess favourable formulation properties.
They thus form crystals more readily than the hydrochloride or the
free base. Further, the crystals of e.g. the L-(-)-hydrogen malate
salt exhibit various polymorphic forms. Polymorphs have different
dissolution rates, milling behaviour and stability, e.g. in
galenical forms where the pharmaceutically active compound is in
solid form, such as tablets or suspensions, and they influence
bioavailability. The surprising presence of polymorphism is
therefore advantageous in terms of improved processability, such as
with polymorph particularly stable thermodynamically, in
formulations with compound in solid form, e.g. tablets or
suspensions, or with polymorph having a particularly high
dissolution rate or solubility, in formulations with dissolved
compound, e.g. nail lacquers. The compounds of the invention are
therefore better processable for e.g. large scale tablet
formulation; they also have favourable penetration/permeation
properties and can thus readily be formulated into topical forms,
such as nail lacquers. Additionally, they possess good solubility
in water and many organic solvents, a prerequisite for good
bioavailability: thus at 25.degree. C., the L-(-)-hydrogen malate
is soluble up to about 12-15 mg/ml in water and>30 mg/ml in
ethyl acetate, as compared with 6.7 mg/ml in water and 0.7 mg/ml in
ethyl acetate for the hydrochloride. Further, they are
non-hygroscopic, thus providing stable formulations while
minimizing the risk of intrinsic chemical breakdown.
[0028] They therefore show a unique combination of good
processability, good solubility and non-hygroscopicity which makes
them remarkably suitable for the preparation of pharmaceutical
compositions of terbinafine.
[0029] The invention further includes:
[0030] a pharmaceutical composition comprising a compound of the
invention together with at least one pharmaceutically acceptable
carrier or diluent;
[0031] a pharmaceutical composition comprising the compound of
formula I in free form or pharmaceutically acceptable salt form
other than a malic acid addition salt form, whenever prepared from
a compound of the invention;
[0032] a compound of the invention for use as a pharmaceutical;
[0033] a compound of the invention for use in the preparation of a
medicament;
[0034] a compound of the invention whenever prepared by a process
as defined above;
[0035] a compound of formula I in free base form or salt form other
than a malic acid addition salt form, whenever prepared from a
compound of the invention;
[0036] the use of a compound of the invention in the preparation of
a medicament for the treatment, e.g. orally, of diseases
susceptible of therapy with the compound of formula I in free base
form or salt form, such as fungal diseases;
[0037] a process for the preparation of a pharmaceutical
composition which comprises mixing a compound of the invention
together with at least one pharmaceutically acceptable carrier or
diluent; and
[0038] a method for the prophylactic or curative treatment of
fungal diseases such as fungal sinusitis infection or
onychomycosis, comprising administration of a therapeutically
effective amount of a compound of the invention to a subject in
need of such treatment.
[0039] Pharmaceutical compositions incorporating a compound of the
invention are preferably compounded in unit dosage form, e.g. by
filling into capsule shells, e.g. soft or hard gelatine capsule
shells, or by tabletting or some other moulding process. Thus unit
dosage forms suitable for administration once or twice daily, e.g.
depending on the particular purpose of therapy, the phase of
therapy, etc., will appropriately comprise half or the total daily
dose contemplated. Such compositions may be administered twice or
three times a week. Preferably the compositions are administered
once-a-day.
[0040] The amount of compound of the invention will of course vary,
e.g. depending on to what extent other components are present, the
mode of administration and the treatment desired. In general,
however, it will be present in an amount within the range of from
about 0.1% to about 35% by weight based on the total weight of the
composition. The total daily dosage of active compound (expressed
in free base equivalent) is, for example, from about 50 mg to about
500 mg daily, e.g. 250 mg daily, or 400 mg, 600 mg or 700 mg daily,
conveniently given, for example, in divided doses up to 4 times a
day. Unit dosage forms comprise e.g. from about 12.5 mg to about
800 mg of compound of the invention (expressed in free base
equivalent) in admixture with at least one solid or liquid
pharmaceutically acceptable carrier or diluent.
[0041] The compounds of the invention may be administered in
similar manner to known standards for use in such indications.
[0042] They may be admixed with conventional, chemotherapeutically
acceptable carriers or diluents and optionally further excipients,
and administered e.g. orally, e.g. in the form of formulations such
as tablets and capsules. A preferred tablet formulation includes a
compound of the invention, a compression aid such as
microcrystalline cellulose, an additive to provide sheen to the
tablet such as anhydrous dibasic calcium phosphate, a disintegrant
such as sodium starch glycolate, and a lubricant such as magnesium
stearate. A preferred capsule formulation includes a compound of
the invention, an inert diluent, a dried disintegrant and a
lubricant as described above.
[0043] Alternatively, they may be administered topically, e.g. in
the form of formulations, e.g. lotions, solutions, ointments or
creams, such as nail lacquers, or parenterally or intravenously.
The concentration of active substance will of course vary, e.g.
depending on the compound of the invention employed, the treatment
desired and the nature of the form or formulation used. In general,
satisfactory results are obtained in e.g. topical formulations at
concentrations of from about 0.1% to about 10%, particularly from
about 0.5% to about 2%, especially about 1% by weight.
[0044] With the present invention there are thus also provided
novel terbinafine compositions containing the compounds of the
invention which meet or substantially reduce the difficulties in
terbinafine therapy hitherto encountered. In particular they may
contain terbinafine in sufficiently high and constant
concentrations to permit convenient oral once-a-day administration,
while at the same time achieving improved safety and tolerability
in terms of fewer Adverse Events.
[0045] Thus the present invention enables reduction of terbinafine
treatment times required to achieve effective therapy, reducing the
exposure time to terbinafine and improving the global safety
profile. In addition it allows closer standardization as well as
optimization of on-going daily dosage requirements for individual
subjects receiving terbinafine therapy as well as for groups of
patients undergoing equivalent therapy. By closer standardization
of individual patient therapeutic regimens, dosaging parameters for
particular patient groups as well as monitoring requirements may be
reduced, thus substantially reducing the cost of therapy.
[0046] Further pharmacokinetic properties of pharmaceutical
compositions containing the compounds of the invention may be
determined in standard animal and human pharmacological
(bioavailability) trials. For example one standard pharmacological
trial may be carried out in healthy male or female non-smoking
volunteers aged between 18 to 45 years having within 20% of the
ideal body weight. The trial may be a single-dose crossover
application. The subjects are domiciled for 24 hours. Blood samples
are taken for 1, 2, 4, 8, 16, 32 and 72 hours after administration
of a pharmaceutical composition containing a compound of the
invention and tested for terbinafine. Terbinafine blood or plasma
concentrations may be determined in conventional manner, e.g. by
HPLC/UV or LC-MS analytical techniques. Safety is judged according
to a standard checklist based on Adverse Event symptoms after 1
week. Preferably the dose of terbinafine salt is 400, 600 or
700-800 mg of base equivalent per day. The safety of terbinafine at
such a dose over the short duration of treatment is remarkable. The
oral compositions of the invention preferably exhibit a C.sub.max
of 100-250%, e.g. 100-150%, of that shown by 250 mg immediate
release terbinafine hydrochloride tablets, e.g. administered as a
single dose and/or in the steady state, e.g. once a day for 7
days.
[0047] Pharmacokinetic drug skin and nail concentration studies may
be carried out according to the same principles as set out for the
above-mentioned standard pharmacological trials. For example a
clinical trial may be effected with daily dosing of compositions
containing a compound of the invention over a 3-week treatment
period.
[0048] Tablets containing the compounds of the invention are useful
for the same indications as for known immediate release terbinafine
hydrochloride tablets. The utility of compounds of the invention
may be observed in standard clinical tests or standard animal
models. For example, one can ascertain dosages of compositions
containing a compound of the invention giving AUC plasma levels of
terbinafine equivalent to AUC plasma levels giving a therapeutic
effect on administration of known terbinafine hydrochloride oral
dosage forms, e.g. a tablet. Pharmaceutical compositions containing
a compound of the invention are particularly and surprisingly
well-tolerated with regard to the Adverse Events mentioned above,
they provoke fewer Adverse Events when co-administered with CYP2D6
substrates such as nortriptyline, desipramine, perphenazine,
metoprolol, encainide and propafenone.
[0049] A randomized double-blind positive-controlled and
placebo-controlled study may e.g. be effected with subjects having
onychomycosis of the toenail confirmed by microscopy and culture.
Treatment is carried out over 12 weeks. Clinical trials may be
effected in several hundred patients to ascertain the freedom from
Adverse Events. However, therapeutic efficacy may already be shown
in trials with 25 patients aged over 12 years. Safety is evaluated
by an Adverse Event report of clinical aspects and vital signs.
Efficacy is determined by microscopy, culture procedures and
visually looking at signs and symptoms. Efficacy is seen in
patients with the fungi described above, especially Trichophyton
rubrum, Trichophyton mentagrophytes and Epidermophyton floccosum.
Patients include those with predisposing factors such as impaired
blood circulation, peripheral neuropathy, diabetes mellitus, damage
from repeated minor trauma, and limited immune defects as well as
AIDS. Patients have (i) distal lateral subungual onychomycosis,
starting at the hyponychium spreading proximally to the nail bed
and matrix, (ii) proximal subungual onychomycosis, wherein the
fungus infects the cuticle and eponychium to reach the matrix where
it becomes enclosed into the nail plate substance, (iii) total
dystrophic onychomycosis, and (iv) superficial white onychomycosis.
If desired plasma concentrations of terbinafine may be evaluated in
conventional manner or as described herein. Concentrations of
terbinafine in the nail may be evaluated from nail clipping
followed by analysis.
EXPLANATION OF THE FIGURES
[0050] FIG. 1: Schematic representation of a Franz cell.
[0051] FIG. 2: Penetration/permeation assay: amount recovered in
receptor chamber (in ng) vs. time (in hours) with 1%
terbinafine-(L)-(-)-hydrogen malate solution: black squares: no
occlusion conditions; black dots: occlusion conditions.
[0052] FIG. 3: X-ray powder diffraction pattern with terbinafine
L-(-)-hydrogen malate polymorph form A (Examples 1 and 3).
[0053] FIG. 4: X-ray powder diffraction pattern with terbinafine
L-(-)-hydrogen malate polymorph form B (Example 2).
[0054] FIG. 5: X-ray powder diffraction pattern with terbinafine
D-(+)-hydrogen malate (Example 4).
[0055] FIG. 6: X-ray powder diffraction pattern with terbinafine
DL-(.+-.)-hydrogen malate (Example 5).
[0056] In FIGS. 3 to 6: cps=signal intensity (counts per second);
Deg.=angle of diffraction (degrees).
[0057] The following Examples illustrate the invention. All
temperatures are in degrees Celsius. m.p.=melting point.
EXAMPLE 1
Terbinafine L-(-)-Hydrogen Malate (Polymorph Form A)
[0058] 15.54 g (53.32 mmoles) terbinafine base and 6.79 g (50.65
mmoles) L-(-)-malic acid are dissolved in 125 ml of ethyl acetate
at 60.degree.. The solution is cooled to 0.degree. and slow
crystallisation takes place. After 2 days standing at 4.degree.
only a few crystals have precipitated. The mixture is then stirred
at 0.degree.. After 8 hours stirring the thick suspension is
diluted with 50 ml of ethyl acetate. The mixture is filtered.
Filtration is very slow. The cake is washed with 60 ml of ethyl
acetate at 0.degree. and dried at 50.degree./10 mbar for 20 hours.
The title compound in form A is obtained (fine white powder; m.p.
.about.96.degree.; solubility at 25.degree.: in ethanol,
ethane/water 2:8 v/v, and ethyl acetate>30 mg/ml; in water
.about.12 mg/ml):
1 Elementary analysis: Calc.: 70.57% C; 7.34% H; 3.29% N; 18.80% O
Found: 70.35% C; 7.39% H; 3.13% N; 18.94% O
[0059] X-ray powder diffraction pattern: see FIG. 3.
EXAMPLE 2
Terbinafine L-(-)-Hydrogen Malate (Polymorph Form B)
[0060] 200.0 g terbinafine base (686.2 mmoles) and 92.02 g
L-(-)-malic acid are dissolved in 1500 ml of ethyl acetate at
60.degree.. The clear solution is then allowed to slowly cool down.
29.2 g terbinafine L-(-)-hydrogen malate form B seed crystals
(obtained as described hereunder) is added at 32.degree. and the
suspension stirred at room temperature (20-25.degree.) for 20
hours. The mixture is then cooled to 3.degree. over 2 hours and
stirred for 4 hours at that temperature. The resultant precipitate
is filtered. The crystals are dried at 50.degree. and 10 mbar for
20 hours. The title compound in form B is obtained (white powder;
m.p.: .about.96.degree.; solubility at 25.degree. in water: 15
mg/ml; [.alpha.].sup.20 at 365 nm=+7.2.degree. in methanol) (as a
control of the positive rotation value, 100 mg salt obtained is
dissolved in 2 ml of methylene chloride, 3 ml NaOH 0.2 N is added,
and the rotation value of the aqueous phase containing free
L-(-)-malic acid is measured: .alpha..sup.20=-0.134.degree. at 546
nm):
2 Elementary analysis: Calc.: 70.57% C; 7.34% H; 3.29% N; 18.80% O
Found: 70.54% C; 7.37% H; 3.26% N; 18.75% O
[0061] X-ray powder diffraction pattern: see FIG. 4.
[0062] Seed crystals of form B are obtained as follows:
[0063] 19.57 g terbinafine base and 8.55 g L-(-)-malic acid are
dissolved in 160 ml of ethyl acetate at 50.degree., the solution is
then cooled to 25.degree. over a period of 1 hour, and seeded with
5 mg terbinafine L-(-)-hydrogen malate (form A) crystals obtained
as described in Example 1; the resultant mixture is allowed to stay
unstirred overnight for 18 hours, then slowly stirred at room
temperature; the resultant gelatinous mixture is warmed to
50.degree. and the resultant clear solution then cooled to
25.degree. and inoculated again, with 10 mg
terbinafine-L-(-)-hydrogen malate form A crystals; the mixture is
allow to rest for 3 days at room temperature without stirring. The
resultant mixture is then gently stirred again and crystallization
slowly sets in. After 24 hours further stirring at room
temperature, the mixture is stirred for 3 hours at 3.degree.,
filtered and dried. Crystalline terbinafine-L-(-)-hydrogen malate
form B is obtained.
EXAMPLE 3
Terbinafine L-(-)-Hydrogen Malate (Polymorph Form A)
[0064] 400.0 g terbinafine base (1.3725 moles) and 180.34 g
L(-)-malic acid (1.3450 moles) are dissolved in 3200 ml of
isopropanol at 35.degree.. The solution is cooled to 25.degree.
over 45 minutes and seeded with 5.72 g terbinafine-L-(-)-hydrogen
malate form A (obtained as described in Example 1). After 27 hours
stirring at room temperature the thick suspension is filtered.
Filtration is slow. The crystals are washed with 500 ml of
isopropanol and dried at 50.degree./15 mbar for 24 hours. The title
compound in form A is obtained (fine white powder; m.p.
.about.96.degree.; solubility at 25.degree. in ethanol>50 mg/ml,
ethylacetate>30 mg/ml; in water .about.12 mg/ml):
3 Elementary analysis: Calc.: 70.57% C; 7.34% H; 3.29% N; 18.80% O
Found: 70.47% C; 7.12% H; 3.40% N; 18.60% O
[0065] X-ray powder diffraction pattern: see FIG. 3.
EXAMPLE 4
Terbinafine D-(+)-Hydrogen Malate
[0066] 8.70 g (29.8 mmoles) terbinafine base and 4.00 g (29.8
mmoles) D(+)-malic acid are dissolved in 100 ml of ethyl acetate at
50.degree.. The clear solution is allowed to slowly cool down and
254 mg terbinafine-D-(+)-hydrogen malate seed crystals (obtained as
described hereunder) is added at 25.degree.. Slow crystallization
takes place and the mixture is stirred at room temperature (20-25)
for 63 hours. The thick suspension is filtered. Filtration is very
slow. The filter cake is washed with 20 ml of ethyl acetate and
dried at 50.degree./10 mbar for 20 hours. The title compound is
obtained (m.p. .about.96.degree.; solubility in water at
25.degree.: .about.7 mg/ml, supersaturation; [.alpha.].sup.20 at
365 nm=.about.7.0.degree. in methanol) (as a control of the
negative rotation value, 100 mg salt obtained is dissolved in 2 ml
of methylene chloride, 3 ml NaOH 0.2 N is added, and the rotation
value of the aqueous phase containing free D-(+)-malic acid is
measured: .alpha..sup.20=.+-.0.137.degree. at 546 nm):
4 Elementary analysis: Calc.: 70.57% C; 7.34% H; 3.29% N; 18.80% O
Found: 70.42% C; 7.45% H; 3.20% N; 18.92% O
[0067] X-ray powder diffraction pattern: see FIG. 5.
[0068] Seed crystals are prepared as follows:
[0069] 4.35 g terbinafine base and 2.00 g D(+)-malic acid are
dissolved in 35 ml of isopropanol at 80.degree.. The solution is
cooled to 25.degree. over a period of 30 minutes, and seeded with
20 mg terbinafine-DL-(.+-.)-malate (obtained as described in
Example 5). A very slow crystallization process takes then place.
After two days stirring at room temperature only a small amount of
crystals has precipitated. The suspension is filtered and the cake
is washed with 5 ml of isopropanol. The crystals are dried at
50.degree./10 mbar for 20 hours. Crystalline
terbinafine-D-(+)-hydrogen malate in obtained.
EXAMPLE 5
Terbinafine DL-(.+-.)-Hydrogen Malate
[0070] A suspension of 8.70 g terbinafine base (29.8 mmoles) and
4.00 g DL-malic acid (29.8 mmoles) in about 70 ml of isopropanol is
heated to 80.degree. and a clear solution is obtained. The solution
is allowed to slowly cool down. 10 mg terbinafine-L-(-)-hydrogen
malate (polymorph form A, obtained as described in Example 1) are
added at 25.degree.. The mixture is stirred for 7 hours at room
temperature. The resultant precipitate is filtered and the filter
cake is washed with 30 ml of isopropanol. The crystals are dried at
50.degree./10 mbar for 20 hours. The title compound is obtained
(white powder; m.p. .about.107.degree.; solubility at 25.degree.:
in ethanol>50 mg/ml; in ethyl acetate .about.17 mg/ml; in water
.about.7 mg/ml):
5 Elementary analysis: Calc.: 70.57% C; 7.34% H; 3.29% N; 18.80% O
Found: 70.49% C; 7.36% H; 3.16% N; 18.82% O
[0071] X-ray powder diffraction pattern: see FIG. 6.
* * * * *