U.S. patent application number 16/019845 was filed with the patent office on 2018-10-25 for method of making dialkyl sulfosuccinate compositions.
The applicant listed for this patent is CYTEC INDUSTRIES INC.. Invention is credited to Lena Kurz, Maureen Mackay, Wolfgang Mohr, Matthias Rischer, Eric Saly.
Application Number | 20180303756 16/019845 |
Document ID | / |
Family ID | 55442903 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180303756 |
Kind Code |
A1 |
Saly; Eric ; et al. |
October 25, 2018 |
METHOD OF MAKING DIALKYL SULFOSUCCINATE COMPOSITIONS
Abstract
A particulate solid composition comprises a blend of dialkyl
sulfosuccinate and a water-soluble polymer. The water-soluble
polymer can be a cellulose ether, a polysaccharide, a polyvinyl
alcohol homopolymer or copolymer, a polyvinyl pyrrolidone
homopolymer or copolymer, a polyvinyl caprolactam polymer or
copolymer, a poly(meth)acrylate, a poly(alkylene oxide) graft
copolymer, or a combination thereof. The particulate solid
composition is free flowing, water-soluble, and dissolves rapidly
in water. It can be made by drying a solution of dialkyl
sulfosuccinate and a water-soluble polymer. The particulate solid
composition can be mixed with organic substances having low water
solubility, for example a generic, a biologic, a biosimilar, an
excipient, a nutraceutical, a medical diagnostic agent, an
agricultural chemical, or a combination thereof, to form
water-soluble compositions.
Inventors: |
Saly; Eric; (Dordrecht,
NL) ; Mackay; Maureen; (Cheshire, GB) ;
Rischer; Matthias; (Frankfurt, DE) ; Mohr;
Wolfgang; (Freiburg i. Br., DE) ; Kurz; Lena;
(Lorrach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CYTEC INDUSTRIES INC. |
Princeton |
NJ |
US |
|
|
Family ID: |
55442903 |
Appl. No.: |
16/019845 |
Filed: |
June 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15046648 |
Feb 18, 2016 |
10022328 |
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16019845 |
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62287198 |
Jan 26, 2016 |
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62118786 |
Feb 20, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1635 20130101;
A61K 9/145 20130101; A61K 9/146 20130101; A61K 9/1647 20130101;
A61K 31/235 20130101; A61K 9/1623 20130101; A61K 9/1641 20130101;
A61K 9/1617 20130101; A61K 31/64 20130101; A61K 9/1652 20130101;
A61K 31/192 20130101; A61K 38/05 20130101 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 38/05 20060101 A61K038/05; A61K 31/64 20060101
A61K031/64; A61K 31/235 20060101 A61K031/235; A61K 31/192 20060101
A61K031/192; A61K 9/14 20060101 A61K009/14 |
Claims
1. A method of making a particulate solid composition, comprising:
mixing a dialkyl sulfosuccinate and a water-soluble polymer in a
solvent to form a solution; contacting the solution with a heated
surface; and removing the solvent to form the particulate solid
composition, wherein the particulate solid composition comprises
flakes, and from 0 to less than 5 weight percent each of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals, based on the total weight of the composition.
2. The method of claim 1, wherein the solvent comprises 0 to 10
weight percent water and 90 to 100 weight percent of a C.sub.1-4
alcohol, based on the total weight of the solvent.
3. The method of claim 1, wherein the dialkyl sulfosuccinate has
the chemical structure: ##STR00003## wherein each of R.sup.1 and
R.sup.2 is independently chosen from a linear or branched
C.sub.4-18 alkyl, C.sub.5-18cycloalkyl, C.sub.7-18 arylalkyl, or
C.sub.6-18 aryl, unsubstituted or substituted by hydroxyl or
C.sub.1-18 alkoxy; and M is an alkali metal, an alkaline earth
metal, an ammonium ion, or a combination thereof, and m is 0.5 when
M is an alkaline earth metal, and m is 1 when M is an alkali metal
or ammonium ion.
4. The method of claim 3, wherein R.sup.1 and R.sup.2 are both
2-ethylhexyl, M is sodium, and m is 1.
5. The method of claim 1, wherein the water-soluble polymer is
natural, semi-synthetic, synthetic, or a combination thereof.
6. The method of claim 1, wherein the water-soluble polymer has a
solubility of greater than or equal to 0.1 gram per liter when
dissolved in pH 1.2 hydrochloric acid buffer for 40 minutes at
37.degree. C.
7. The method of claim 1, wherein the water-soluble polymer has a
solubility of greater than 0.1 gram per liter when dissolved in pH
6.8 phosphate buffer for 40 minutes at 37.degree. C.
8. The method of claim 1, wherein the water-soluble polymer
comprises a cellulose ether, a polysaccharide, a polyvinyl alcohol
homopolymer or copolymer, a polyvinyl pyrrolidone homopolymer or
copolymer, a polyvinyl caprolactam polymer or copolymer, a
poly(meth)acrylate, a poly(alkylene oxide) graft copolymer, or a
combination thereof.
9. The method of claim 1, wherein the water-soluble polymer
comprises hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
poly(vinyl pyrrolidone), poly(vinyl pyrrolidone-co-vinyl acetate),
polyvinyl alcohol, poly(vinyl acetate-co-vinyl alcohol),
poly(ethylene oxide-co-vinyl acetate-co-vinyl caprolactam), or a
combination thereof.
10. A particulate solid composition made by the method of claim
1.
11. The particulate solid composition according to claim 10,
wherein the particulate solid composition is free of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals.
12. The particulate solid composition according to claim 10,
further comprising 0 to 5 weight percent of polysaccharides, sugar
alcohols, sodium benzoate, and sodium sulfate combined.
13. The particulate solid composition of claim 10, comprising
flakes having a thickness from 1 to 100 micrometers, as determined
by scanning electron microscopy.
14. The particulate solid composition of claim 10, consisting
essentially of 10 to 70 weight percent sodium dioctyl
sulfosuccinate and 30 to 90 weight percent of a water-soluble
polymer comprising poly(vinylpyrrolidone-co-vinyl acetate),
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or a
combination thereof, based on the total weight of the sodium
dioctyl sulfosuccinate and the water-soluble polymer.
15. The particulate solid composition of claim 10, wherein the
flakes comprise both the dialkyl sulfosuccinate and the
water-soluble polymer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 15/046,648, filed Feb. 18, 2016 (allowed), which claims
priority to U.S. Provisional Application Nos. 62/287,198, filed
Jan. 26, 2016 (expired), and 62/118,786, filed Feb. 20, 2015
(expired), each of which is incorporated herein by reference in
their entirety.
BACKGROUND OF THE INVENTION
[0002] Dialkyl sulfosuccinates are a class of surfactants used as
emulsifiers, dispersants, wetting agents, and adjuvants. An example
of a dialkyl sulfosuccinate is sodium dioctyl sulfosuccinate
(DOSS). DOSS is a waxy, sticky, granular solid, which is difficult
to handle. It tends to form lumps upon storage, and is slow to
dissolve in solvents. Therefore it is often supplied in solution
form, dissolved in organic solvent, water, or organic solvent-water
combinations, for example ethanol-water and propylene glycol-water.
DOSS can also be mixed with a solid diluent, for example sodium
benzoate (SB), to produce a mixture (DOSS-SB) with reduced
stickiness and improved water dissolution rate. However, the water
solubility and dissolution rates of DOSS-SB mixtures are still low.
Sodium benzoate is used as a food preservative and is
pharmacologically active. However, its use as an excipient for
other active pharmaceutical ingredients can be undesirable, because
it is not biologically inert, and because of the risk of formation
of benzene from sodium benzoate in the presence of ascorbic
acid.
[0003] A dialkyl sulfosuccinate composition containing a solid
diluent that is free of sodium benzoate, and yet is not waxy or
sticky, has good flowability and water solubility, and dissolves
rapidly in water, is desirable. Also, the surface and wetting
activity of the dialkyl sulfosuccinate, as indicated by critical
micelle concentration and contact angle of aqueous solutions of the
dialkyl sulfosuccinate with various substrates, should not be
adversely affected by the solid diluent.
BRIEF DESCRIPTION OF THE INVENTION
[0004] A particulate solid composition comprises a blend of dialkyl
sulfosuccinate and a water-soluble polymer.
[0005] A method of making a particulate solid composition,
comprises: mixing a dialkyl sulfosuccinate and a water-soluble
polymer in a solvent to form a solution, and spray drying the
solution to form the particulate solid composition, wherein: the
particulate solid composition comprises primary particles having a
diameter range from 1 to 50 micrometers, as measured by scanning
electron microscopy; and comprises, based on the total weight of
the composition, 0 to less than 5 weight percent each of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals.
[0006] A method of making a particulate solid composition,
comprises: mixing a dialkyl sulfosuccinate and a water-soluble
polymer in a solvent to form a solution; contacting the solution
with a heated surface; and removing the solvent to form the
particulate solid composition, wherein the particulate solid
composition comprises flakes, and comprises, based on the total
weight of the composition, 0 to less than 5 weight percent each of
active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals.
[0007] A method of making a water-soluble composition, comprises
mixing a particulate solid composition and an organic substance
having low water solubility, in amounts effective to form the
water-soluble composition; wherein: the particulate solid
composition comprises a blend of dialkyl sulfosuccinate, a
water-soluble polymer, and 0 to less than 5 weight percent each of
active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals, based on the total weight of the
water-soluble composition; the particulate solid composition has a
distilled water solubility of 1 to 20 weight percent at 23.degree.
C., with no haze; and the organic substance has a water solubility
of less than 1 weight percent at 23.degree. C.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Referring now to the drawings:
[0009] FIG. 1 depicts photographs of DOSS (right), HPMC (center),
and the DOS-HPMC of Example 3 (left).
[0010] FIG. 2 depicts photographs of DOSS (right), copovidone
(center), and the DOSS-copovidone of Example 5 (left).
[0011] FIG. 3a, FIG. 3b, and FIG. 3c depict SEM photographs of the
DOSS-HPMC of Example 3 at magnifications of 500.times.,
3,000.times. and 5,000.times., respectively.
[0012] FIG. 4a, FIG. 4b, and FIG. 4c depict SEM photographs of the
DOSS-copovidone of Example 3 at magnifications of 1,000.times.,
2,000.times. and 5,000.times., respectively.
[0013] FIG. 5a, FIG. 5b, and FIG. 5c depict SEM photographs of the
DOSS-SB of Comparative Example 1 at magnifications of 200.times.,
500.times. and 1,000.times., respectively.
[0014] FIG. 6 is a plot of surface tension in millinewtons per
meter (mN/m) as a function of concentration in weight percent (wt.
%), for DOSS-HPMC (Example 3), DOSS-copovidone (Example 5), and
DOSS-SB (Comparative Example 1).
[0015] FIG. 7 depicts individual powder X-ray diffraction patterns
for DOSS and copovidone, overlaid.
[0016] FIG. 8 depicts the powder X-ray diffraction pattern for
DOSS-copovidone prepared by vacuum drum drying.
[0017] FIG. 9 depicts individual powder X-ray diffraction patterns
for DOSS and HPMC, overlaid.
[0018] FIG. 10 depicts the powder X-ray diffraction pattern for
DOSS-HPMC prepared by spray drying.
[0019] FIG. 11 is an SEM micrograph of the DOSS-copovidone of
Example 8 at a magnification of 250.times..
[0020] FIG. 12 is an SEM micrograph of the DOSS-copovidone of
Example 8 at a magnification of 500.times..
[0021] FIG. 13 is an SEM micrograph of the DOSS-copovidone of
Example 8 at a magnification of 1000.times..
[0022] FIG. 14 depicts visible micrographs and FTIR vibrational
images, measured in reflectance mode, of two samples of DOSS-HPMC
particles with a 350.times.350 micrometer field of view. FIGS.
14-1, 14-2, and 14-3 are two-dimensional visible, DOSS-specific
FTIR, and HPMC-specific FTIR images of a first sample, and FIGS.
14-4, 14-5, and 14-6 are two-dimensional visible, DOSS-specific
FTIR, and HPMC-specific FTIR images of a second sample. FIG. 14-7
and FIG. 14-8 are three-dimensional HPMC-specific and DOSS-specific
FTIR images for the first sample. FIG. 14-9 depicts overlaid
one-dimensional FTIR spectra of DOSS and HPMC indicating the
analytical wavelengths of 1735 and 1064 cm.sup.-1, respectively,
which were used to generate the two- and three-dimensional images
of FIGS. 14-2, 14-3, and 14-5 to 14-8.
[0023] FIG. 15 depicts FTIR attenuated total reflectance (ATR)
images of a sample of DOSS-HPMC with a 70.times.70 micrometer field
of view, including a DOSS-specific image (FIG. 15-1), an
HPMC-specific image (FIG. 15-2), and a 25.times.47 micrometer
HPMC-normalized DOSS distribution image (FIG. 15-3).
[0024] FIG. 16 depicts a visible micrograph (FIG. 16-1) and FTIR
vibrational images, measured in transmission mode, of a sample of
DOSS-HPMC with a 350.times.350 micrometer field of view, including
a DOSS-specific image (FIG. 16-2), an HPMC-specific image (FIG.
16-3), and an HMPC-normalized DOSS distribution image with a
110.times.110 micrometer field of view (FIG. 16-4).
[0025] FIG. 17 depicts a visible micrograph (FIG. 17-5) and FTIR
vibrational images, measured in transmission mode, of compressed
particle aggregates of DOSS-copovidone with 350.times.350
micrometer fields of view, including DOSS-specific images (FIGS.
17-1 and 17-2) and copovidone-specific images (FIGS. 17-3 and
17-6). The DOSS-specific image of FIG. 17-1 was generated at an
analytical wavelength of 2958 cm.sup.-1; the DOSS-specific image of
FIG. 17-2 was generated at 2874 cm.sup.-1; and the
copovidone-specific images of FIGS. 17-3 and 17-6 were generated at
1494 cm.sup.-1. FIG. 17-6 is a three-dimensional image of
copovidone distribution. FIG. 17-4 depicts overlaid one-dimensional
FTIR spectra of DOSS and copovidone, indicating the analytical
wavelengths of 2874 and 2958 cm.sup.-1 for DOSS, which were used to
generate the two-dimensional images of FIGS. 17-1 and 17-2,
respectively; and the analytical wavelength of 1094 cm.sup.-1,
which was used to generate the two-dimensional image of FIG. 17-3
and the three-dimensional image of FIG. 17-6.
[0026] FIG. 18 depicts a visible micrograph (FIG. 18-1) and FTIR
vibrational images, measured in transmission mode, of a compressed
sample of DOSS-copovidone with a 350.times.350 micrometer field of
view, including DOSS-specific images (FIGS. 18-2 and 18-3) and
copovidone-specific images (FIGS. 18-4 and 18-5). The DOSS-specific
image of FIG. 18-2 was generated at an analytical wavelength of
2874 cm.sup.-1; and the copovidone-specific image of FIG. 18-4 was
generated at 1494 cm.sup.-1. FIGS. 18-3 and 18-5 are
three-dimensional images of the DOSS and copovidone distributions,
respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Dialkyl sulfosuccinates, for example, sodium dioctyl
sulfosuccinate (DOSS) are generally supplied mixed with liquid or
solid diluents, for example sodium benzoate (SB), to improve
handling. Typically pure DOSS is in the form of sticky, waxy
flakes. The present inventors have made dialkyl sulfosuccinate
powder blends in which the diluent is a water-soluble polymer. When
spray-dried or vacuum drum dried, the present dialkyl
sulfosuccinate powder blends are microscopic, spherical or flake
particles with an amorphous matrix in which the crystalline DOSS is
dispersed. Advantageously, the dialkyl sulfosuccinate blends are
free-flowing, water-soluble solids which dissolve rapidly in water.
Moreover, the surface and wetting activity of the dialkyl
sulfosuccinate, as indicated by critical micelle concentration and
contact angle of aqueous solutions of the dialkyl sulfosuccinate
with various substrates, is not adversely affected by the
water-soluble polymer.
[0028] The inventors have found a particulate solid composition
comprising a blend of dialkyl sulfosuccinate and a water-soluble
polymer. The dialkyl sulfosuccinate has the chemical structure:
##STR00001##
wherein R.sup.1 and R.sup.2 are each independently a linear or
branched, C.sub.4-18 alkyl, specifically C.sub.4-12 alkyl, more
specifically C.sub.4-8 alkyl, C.sub.5-18 cycloalkyl, C.sub.7-18
arylalkyl, or C.sub.6-18 aryl, unsubstituted or substituted by
hydroxyl or C.sub.1-18 alkoxy, more specifically C.sub.1-4 alkoxy.
The cation "M" can be an ammonium or quaternary ammonium ion. In
some embodiments, M is an alkali metal, an alkaline earth metal, an
ammonium ion, or a combination thereof, and m is 0.5 when M is an
alkaline earth metal, and m is 1 when M is an alkali metal or
ammonium ion. M can be for example, lithium sodium, potassium, or
calcium. In some embodiments, M is sodium. In some embodiments,
R.sup.1 and R.sup.2 are each independently a linear or branched
C.sub.4-12 alkyl, specifically C.sub.4-8 alkyl. For example,
R.sup.1 and R.sup.2 can each independently be amyl, hexyl, octyl,
nonyl, dodecyl, or stearyl. Since these alkyl groups can be
branched, octyl can be 2-ethylhexyl. Thus in some embodiments,
R.sup.1 and R.sup.2 are both 2-ethylhexyl, M is sodium, and m is 1.
This specific dialkyl sulfosuccinate is known as "sodium dioctyl
sulfosuccinate", and is referred to herein as "DOSS". DOSS is
available from Solvay S.A. as Docusate Sodium.
[0029] The particulate solid composition comprises a water-soluble
polymer. The water soluble polymer can be natural, semi-synthetic,
synthetic, or a combination thereof. Natural water soluble polymers
include albumin, and polysaccharides such as xanthan gum, pectin,
dextran, carrageenan, guar gum, galactomannan, alginate, xanthan
gum, starch, hyaluronic acid, chitin, and chitosan. Semi-synthetic
water soluble polymers include starch derivatives (blends or
chemically modified), for example a cyclodextrin. Semi-synthetic
water soluble polymers can also include chemically modified
cellulose, for example hydroxypropylmethyl cellulose (HPMC),
hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and
sodium carboxy methyl cellulose (Na-CMC).
[0030] Synthetic water-soluble polymers include addition polymers
of ethylenically unsaturated monomers, and can be homopolymers or
copolymers, for example, a random copolymer, an alternating
copolymer, a periodic copolymer, a block copolymer, a graft
copolymer, or a branched copolymer. The water-soluble polymer
architecture can be, for example, star, comb, brush, or dendritic.
Examples of synthetic water-soluble addition polymers include
polyvinyl alcohol homopolymers and copolymers, poly(vinyl
pyrrolidone) homopolymers and copolymers, poly(vinyl caprolactam)
homopolymers and copolymers, poly (meth)acrylic acid homopolymers
and copolymers, poly(meth)acrylamide homopolymers and copolymers,
polyoxazoline homopolymers and copolymers, vinyl ether homopolymers
and copolymers, and polymaleic anhydride homopolymers and
copolymers. Other examples of synthetic water-soluble polymers
include poly(alkylene oxide) homopolymers and copolymers, for
example poloxamers, polyphosphates, and polyphosphazenes.
[0031] In particular, the water-soluble polymer can comprise a
cellulose ether, a polysaccharide, a polyvinyl alcohol homopolymer
or copolymer, a poly(vinyl pyrrolidone) homopolymer or copolymer, a
polyvinyl caprolactam polymer or copolymer, a poly(meth)acrylate, a
poly(alkylene oxide), a poly(alkylene oxide) block or graft
copolymer, or a combination thereof. In some embodiments, the
water-soluble polymer comprises hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, poly(vinyl pyrrolidone), poly(vinyl
pyrrolidone-co-vinyl acetate), polyvinyl alcohol, poly(vinyl
acetate-co-vinyl alcohol), poly(ethylene oxide-co-vinyl
acetate-co-vinyl caprolactam), or a combination thereof.
[0032] In some embodiments, the water-soluble polymer is
hydroxypropylmethyl cellulose (HPMC). An example of HPMC is
PHARMACOAT.TM. 603, having a methoxy content of 28.0 to 30.0 weight
percent, a hydroxypropoxy content of 7.0 to 12.0 wt %, and a
viscosity of 2.4 to 3.6 mPas, available from Shin-Etsu
Chemical.
[0033] The water-solubility of poly(vinyl pyrrolidone-co-vinyl
acetate) depends on the vinyl pyrrolidone/vinyl acetate comonomer
ratio. Thus, the water-soluble polymer can comprise poly(vinyl
pyrrolidone-co-vinyl acetate) having copolymerized vinyl
pyrrolidone and vinyl acetate repeat units in a 50:50 to 99:1
weight ratio. In some embodiments, the water-soluble polymer
comprises poly(vinyl pyrrolidone-co-vinyl acetate) having
copolymerized vinyl pyrrolidone and vinyl acetate repeat units in a
6:4 weight ratio, which is commercially available from BASF as
KOLLIDON.TM. VA 64.
[0034] In some embodiments, the polymers are defined as water
soluble if the solubility is greater than or equal to 0.1 g/L when
dissolved in pH 1.2 HCl buffer for 40 minutes at 37.degree. C.
Within this range the solubility can be greater than 1 g/L, or
greater than 10 g/L, and less than 1,000 g/L, less than 900 g/L,
less than 800 g/L, less than 700 g/L, less than 600 g/L, or less
than 500 g/L. In some embodiments the polymers are defined as water
soluble if the solubility is greater than 0.1 g/L when dissolved in
pH 6.8 phosphate buffer for 40 minutes at 37.degree. C. Within this
range the solubility can be greater than 1 g/L, or greater than 10
g/L, and less than 1,000 g/L, less than 900 g/L, less than 800 g/L,
less than 700 g/L, less than 600 g/L, or less than 500 g/L. The
water-soluble polymer can be miscible with pH 1.2 HCl and pH 6.8
phosphate buffers in all proportions. However, as the water-soluble
polymer concentration is increased, the resulting solution can
become so viscous at 37.degree. C. that the solution can no longer
be stirred. As a practical matter, the upper limit in solubility
can be determined by this phenomenon. An example of a water-soluble
polymer that is soluble in pH 1.2 HCl buffer is poly(butyl
methacrylate-co-2-dimethylaminoethyl methacrylate-co-methyl
methacrylate), having copolymerized 2-dimethylaminoethyl
methacrylate, butyl methacrylate, and methyl methacrylate repeat
units in a 2:1:1 weight ratio, respectively, which is commercially
available as EUDRAGIT.TM. E PO.
[0035] The particle morphology of the particulate solid composition
can depend on the method of making the composition. For example,
spherical particles can be obtained by spray drying. Thus in some
embodiments, the particulate solid composition is composed of
primary particles that are microscopic and spherical. The particle
diameter range can be from 1 to 50 micrometers, as determined by
scanning electron microscopy (SEM). Within this range, the particle
diameter range can be 1 to 40 micrometers, specifically 1 to 30
micrometers. In some embodiments, the particle diameter range is 1
to 25 micrometers, specifically 2 to 25 micrometers, and more
specifically 2 to 15 micrometers.
[0036] FIG. 3a, FIG. 3b, and FIG. 3c depict SEM photographs of the
DOSS-HPMC of Example 3 at magnifications of 500.times.,
3,000.times. and 5,000.times., respectively. FIG. 4a, FIG. 4b, and
FIG. 4c depict SEM photographs of the DOSS-copovidone of Example 3
at magnifications of 1,000.times., 2,000.times. and 5,000.times.,
respectively. FIG. 5a, FIG. 5b, and FIG. 5c depict SEM photographs
of the DOSS-SB of Comparative Example 1 at magnifications of
200.times., 500.times. and 1,000.times., respectively. As can be
seen from the SEM photographs, the DOSS-HPMC and DOSS-copovidone
particles are spherical, while the DOSS-SB particles are
irregularly-shaped. HPMC particles were macroscopic and
irregularly-shaped. Advantageously, the DOSS-HPMC and
DOSS-copovidone blends have a particle diameter range of 2 to 15
micrometers, while the DOSS-SB blend has a particle diameter range
of about 100 micrometers and above, as determined by SEM.
[0037] Under some conditions, the primary particles, once formed,
can combine to form agglomerates. Thus in some embodiments, the
particulate solid composition further comprises aggregates of the
primary particles, wherein the aggregates have a diameter range
from 0.1 to 2 millimeters, as determined by optical microscopy.
Within this range, the particle diameter of the aggregates can be
0.1 to 1 millimeters.
[0038] As mentioned above, the particle morphology of the
particulate solid composition can depend on the method of making
the composition. For example, flat particles can be obtained by
drum drying. Thus in some embodiments, the particulate solid
composition comprises flakes. The flakes can be irregular in shape,
and can have a thickness of 1 to 100 micrometers, as determined by
scanning electron microscopy. Within this range, the flakes can
have a thickness of 1 to 50 micrometers, 1 to 20 micrometers, or 1
to 10 micrometers. In some embodiments, the flakes have a thickness
of 1 to 10 micrometers. The flakes can be obtained, for example by
vacuum drum drying.
[0039] The particulate solid composition can be amorphous.
Amorphous particles lack the long-range inter-molecular order of
crystalline solids, and lack sharp crystalline X-ray diffraction
(XRD) peaks. This is in contrast to physical mixtures of dioctyl
sulfosuccinate and sodium benzoate, which can be crystalline.
[0040] In some embodiments, the particulate solid composition
comprises a blend of crystalline dialkyl sulfosuccinate and
amorphous or semi-crystalline water-soluble polymer. Powder X-ray
diffraction (PXRD) was used to assess the crystallinity of the
compositions. The diffraction patterns of, for example
DOSS-copovidone and DOSS-HPMC, both indicate the presence of both
crystalline DOSS and amorphous or semi-crystalline copovidone or
HPMC in the compositions.
[0041] In some embodiments, the amorphous particulate solid
composition comprises 10 to 90 weight percent of the dialkyl
sulfosuccinate and 10 to 90 weight percent of the water-soluble
polymer, based on the total weight of the dialkyl sulfosuccinate
and water-soluble polymer. Within this range, the particulate solid
composition can comprise greater than or equal to 20 or 30 weight
percent and less than or equal to 80 or 70 weight percent of
dialkyl sulfosuccinate, and greater than or equal to 20 or 30
weight percent and less than or equal to 80 or 70 weight percent of
water-soluble polymer. For example, the particulate solid
composition can comprise 10 to 70 weight percent, 20 to 50 weight
percent, or 20 to 40 weight percent of the dialkyl sulfosuccinate,
and 30 to 90 weight percent, 50 to 80 weight percent, or 60 to 80
weight percent of the water-soluble polymer, based on the total
weight of the dialkyl sulfosuccinate and water-soluble polymer. In
some embodiments, the particulate solid composition comprises 50 to
70 weight percent of the dialkyl sulfosuccinate, and 30 to 50
weight percent of the water-soluble polymer; or 20 to 40 weight
percent of the dialkyl sulfosuccinate, and 60 to 80 weight percent
of the water-soluble polymer, based on the total weight of the
dialkyl sulfosuccinate and the water-soluble polymer.
[0042] It is desirable that the amount of any substances other than
the blend of dialkyl sulfosuccinate and a water-soluble polymer be
minimized. In this way, the particulate solid composition can be
used to solubilize organic substances having a water solubility of
less than 1 weight percent at 25.degree. C. without undue
contamination of the organic substance. Thus, the particulate solid
composition can comprise 0 to 80 weight percent each, based on the
total weight of the particulate solid composition, of active
pharmaceutical ingredients, generics, biosimilars, excipients,
nutraceuticals, diagnostic agents, and agricultural chemicals.
Within this range, the particulate solid composition can comprise 0
to 70, 60, 50, 40, 30, 20, 10, 2, 1, 0.5, or 0.1 weight percent
each, based on the total weight of the particulate solid
composition, of active pharmaceutical ingredients, generics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals. In some embodiments, the particulate solid
composition comprises 0 to 40 weight percent each, based on the
total weight of the particulate solid composition, of active
pharmaceutical ingredients, generics, biosimilars, excipients,
nutraceuticals, diagnostic agents, and agricultural chemicals. In
some embodiments, the particulate solid composition is free of
active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals, which means that there is no measurable
amount of these materials. Agricultural chemicals include, for
example, pesticides, insecticides, herbicides, biocides, and
antifungals.
[0043] The particulate solid composition can comprise little or no
excipient other than the sodium dioctyl sulfosuccinate, for example
polysaccharides, sugar alcohols, sodium benzoate, and sodium
sulfate. Thus, in some embodiments, the particulate solid
composition further comprises 0 to 5 weight percent, 0 to 3 weight
percent, 0 to 1 weight percent, 0 to 0.5 weight percent, or 0 to
0.1 weight percent each of polysaccharides, sugar alcohols, sodium
benzoate, and sodium sulfate. In some embodiments, the particulate
solid composition is free of polysaccharides, sugar alcohols,
sodium benzoate, and sodium sulfate.
[0044] The particulate solid composition has many advantageous
properties. For example, it is free flowing, water-soluble, and
dissolves rapidly in water. Moreover, the critical micelle
concentration of the dialkyl sulfosuccinate is not adversely
affected. Advantageously, the free flowing particulate solid
composition is easily removed from its packaging or container, with
minimal particle aggregation. Thus, in some embodiments, the
particulate solid composition is free flowing. Photographs of
DOSS-HPMC and DOSS-copovidone blends are reproduced in FIG. 1
(left) and 2 (left), respectively.
[0045] Advantageously, the particulate solid composition is
water-soluble. Thus, in some embodiments the particulate solid
composition has a distilled water solubility of 1 to 20 weight
percent at 23.degree. C., with no haze. Within this range, the
particulate solid composition can have a distilled water-solubility
of 1 to 10 weight percent, specifically 2 to 10 weight percent, and
more specifically 5 to 10 weight percent at 23.degree. C., with no
haze. In some embodiments, the particulate solid composition has a
distilled water solubility of at least 10 g/L at 23.degree. C.,
with no haze. Within this range, the particulate solid composition
can have a distilled water solubility of at least 30, 50, 70, 90 or
100 g/L and less than 1000, 900, 800, 700, 600, 500, 400, 300, or
200 g/L at 23.degree. C.
[0046] Moreover, the particulate solid composition dissolves
rapidly in water. Thus in some embodiments, 3 parts by weight of
the particulate solid composition has a dissolution time in 87
parts by weight distilled water at 23.degree. C. of less than 20
minutes. Within this range, the particulate solid composition can
have a dissolution time in distilled water of greater than 0.1 or 1
minute and less than 15, 10, 5, 4, or 3 minutes.
[0047] Advantageously, the particulate solid composition also has a
rapid dissolution rate under physiological conditions, for example
at the pH of human stomach acid. For example, 3 parts by weight of
the particulate solid composition can have a dissolution time in 87
parts by weight of 0.1 M hydrochloric acid at 23.degree. C., of
less than 20 minutes. 0.1 M hydrochloric acid has a pH comparable
to the pH of stomach acid. Within this range, the particulate solid
composition can have a dissolution time in 0.1 M hydrochloric acid
of less than 15 minutes, specifically less than 10, 5, 4, or 3
minutes.
[0048] In some specific embodiments, the particulate solid
composition consists essentially of 10 to 70 weight percent sodium
dioctyl sulfosuccinate and 30 to 90 weight percent of a
water-soluble polymer comprising poly(vinylpyrrolidone-co-vinyl
acetate), hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
or a combination thereof, based on the total weight of the dioctyl
sodium sulfosuccinate and the water-soluble polymer.
[0049] The particulate solid composition is distinguished from a
physical mixture of individual dialkyl sulfosuccinate particles and
water-soluble polymer particles, in that individual particles
comprise both dialkyl sulfosuccinate and water-soluble polymer.
[0050] The particulate solid composition can be prepared by
dissolving dialkyl sulfosuccinate and water-soluble polymer in a
solvent, and removal of the solvent (drying). Solvent removal can
be done by a variety of methods, including hot air drying, indirect
drying, and freeze drying. Hot air, also known as convective or
direct drying, involves the application of a stream of hot, dry air
to the solution to be dried. An example of hot air drying is spray
drying. In some embodiments, the particulate solid composition is
prepared by spray drying a solution of the dialkyl sulfosuccinate
and water-soluble polymer in a solvent. Thus, a method of making
the particulate solid composition comprises mixing a dialkyl
sulfosuccinate and a water-soluble polymer in a solvent to form a
solution, and spray drying the solution to form the particulate
solid composition, wherein the particulate solid composition
comprises primary particles having a diameter range from 1 to 50
micrometers, and comprises, based on the total weight of the
composition, 0 to 5 weight percent each of active pharmaceutical
ingredients, generics, biologics, biosimilars, nutraceuticals,
excipients, diagnostic agents, and agricultural chemicals.
[0051] The particulate solid composition made by spray drying
comprises primary particles having a diameter range from 1 to 50
micrometers, as measured by scanning electron microscopy; and
comprises, based on the total weight of the composition, 0 to less
than 5 weight percent each of active pharmaceutical ingredients,
generics, biologics, biosimilars, excipients, nutraceuticals,
diagnostic agents, and agricultural chemicals. The particulate
solid composition made by the method can further comprise
aggregates of the primary particles, wherein the aggregates have a
diameter range from 0.1 to 2 millimeters, as determined by optical
microscopy.
[0052] The solvent can be water or an organic solvent. In some
embodiments, the solvent is water, or mixtures of water and a polar
organic solvent, for example a C.sub.1-4 alcohol selected from
methanol, ethanol, 2-propanol, 2-methyl-1-propanol,
2-methyl-2-propanol, 1-butanol, 2-butanol, and combinations
thereof, acetone, methyl ethyl ketone, dimethyoxyethane,
tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethyl
sulfoxide, acetonitrile, or a combination thereof. In some
embodiments, the solvent comprises 0 to 10 weight percent water and
90 to 100 weight percent of a C.sub.1-4 alcohol, for example
ethanol, based on the total weight of the solvent. Prior to spray
drying, the solution solids can be 1 to 80 weight percent. Within
this range the solution solids can be 1 to 70 weight percent,
specifically 1 to 50 weight percent, 1 to 30 weight percent, 1 to
20 weight percent, or 1 to 10 weight percent. The solutions can be
spray dried using commercially available equipment, for example a
cyclone dryer. The inlet temperature depends upon the solvent
boiling point and the decomposition temperatures of the dialkyl
sulfosuccinate and water-soluble polymer. The inlet temperature can
be 50 to 250.degree. C., specifically 100 to 200.degree. C. The
outlet temperature can be 20 to 200.degree. C., specifically 30 to
100.degree. C. Advantageously, spray drying provides particulate
solid compositions that are free-flowing, water-soluble, and which
dissolve rapidly in water.
[0053] Indirect drying, also known as contact drying, involves
heating the solution through a hot wall in contact with the
solution. An example of indirect drying is drum drying. In some
embodiments, the particulate solid composition is prepared by
vacuum drum drying a solution of the dialkyl sulfosuccinate and
water-soluble polymer in a solvent. Thus a method of making a
particulate solid composition comprises: mixing a dialkyl
sulfosuccinate and a water-soluble polymer in a solvent to form a
solution; contacting the solution with a heated surface; and
removing the solvent to form the particulate solid composition,
wherein the particulate solid composition comprises, based on the
total weight of the composition, 0 to less than 5 weight percent
each of active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals. The solvents and solids contents can be the
same as described above for spray drying. Indirect drying can be
done under atmospheric pressure or under a partial vacuum, for
example at a pressure of 10 to 760 mm Hg, specifically 50 to 720 mm
Hg, and at a temperature of 20 to 150.degree. C., specifically 50
to 150.degree. C. In some embodiments, processability of the
solution is improved when the solvent comprises ethanol. For
example, it has surprisingly been found that a solution of sodium
dioctyl sulfosuccinate and water-soluble polymer can be readily
dried by vacuum drum drying when the solvent comprises ethanol,
while vacuum drum drying is problematic when the solvent is
water.
[0054] The particulate solid composition made by drum drying
comprises flakes, and comprises, based on the total weight of the
composition, 0 to less than 5 weight percent each of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals. The flakes can have a thickness of 1 to 100 micrometers,
as determined by scanning electron microscopy.
[0055] Advantageously, these methods provide particulate solid
compositions that have a low volatiles content. For example, after
drying, the dialkyl sulfosuccinate water-soluble polymer blend can
have a solids content of 95 to 100 weight percent. Within this
range, the dialkyl sulfosuccinate water-soluble polymer blend can
have a solids content of 98 to 100 weight percent, specifically 99
to 100 weight percent.
[0056] Thus in some embodiments, the particulate solid composition
is made by mixing a dialkyl sulfosuccinate and a water-soluble
polymer in a solvent to form a solution, and spray drying the
solution to form the particulate solid composition, wherein the
particulate solid composition comprises primary particles having a
diameter range from 1 to 50 micrometers, as measured by scanning
electron microscopy, and comprises, based on the total weight of
the composition, 0 to less than 5 weight percent each of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals. All of the compositional and physical property
variations of the particulate solid composition described above
apply as well to the particulate solid composition produced by this
method. For example, the particulate solid composition prepared by
the method can further comprise aggregates of the primary
particles, wherein the aggregates have a diameter range from 0.1 to
2 millimeters, as determined by optical microscopy.
[0057] The particulate solid compositions are particularly useful
for improving the water solubility of organic substances having low
water solubility. The organic substance, can be, for example, a
natural product, a chemical compound, an oligomer, a polymer, a
peptide, or a combination thereof. The organic substance can have a
water solubility of 0 to less than 5 weight percent in water.
Within this range, the organic compound or polymer can have a water
solubility of 0 to less than 2 weight percent, 0 to less than 1
weight percent, 0 to less than 0.5 weight percent, 0 to less than
0.1 weight percent, or 0 to less than 0.01 weight percent.
[0058] Thus, a method of making a water-soluble composition
comprises mixing an particulate solid composition and an organic
substance having low water solubility, in amounts effective to form
the water-soluble composition; wherein: the particulate solid
composition comprises a blend of dialkyl sulfosuccinate and a
water-soluble polymer comprising primary particles, wherein the
primary particles have a diameter range from 1 to 50 micrometers,
as determined by scanning electron microscopy; and 0 to less than 5
weight percent each of active pharmaceutical ingredients, generics,
biologics, biosimilars, excipients, nutraceuticals, diagnostic
agents, and agricultural chemicals, based on the total weight of
the water-soluble composition; the particulate solid composition
has a distilled water solubility of 1 to 20 weight percent at
23.degree. C., with no haze; and the organic substance has a water
solubility of less than 1 weight percent at 23.degree. C.
[0059] The mixing can be done by methods known in the art,
including blending, for example convection blending, dispersion
blending, and shear blending, milling, for example wet ball
milling, spray drying, gas fluidized bed drying, extrusion, for
example hot melt extrusion, coating, and tableting. Spray drying
and gas fluidized bed drying can be conducted on solutions of the
particulate solid composition and organic substance in a solvent,
for example water. In some embodiments, the mixing is done by hot
melt extrusion.
[0060] Advantageously, the particulate solid composition can be
used to improve the water solubility of a wide variety of organic
substances, including active pharmaceutical ingredients, generics,
biologics, biosimilars, excipients, nutraceuticals, diagnostic
agents, or agricultural chemicals. Thus in some embodiments, the
organic substance comprises an active pharmaceutical ingredient, a
generic, a biologic, a biosimilar, an excipient, a nutraceutical,
diagnostic agent, or an agricultural chemical. The water-soluble
composition can have other advantageous properties for in vivo use,
for example improved in vivo dissolution rate, resorption, and
bioavailability at physiological pH values. The particulate solid
composition can also be used to improve the water solubility,
dispersion, or wetting of a wide variety of other useful materials,
including food additives, inks, pigments, dyes, stabilizers, and
oils, to name a few.
[0061] This invention includes at least the following
embodiments.
Embodiment 1
[0062] A particulate solid composition comprising a blend of
dialkyl sulfosuccinate and a water-soluble polymer.
Embodiment 2
[0063] The particulate solid composition of embodiment 1, wherein
the water-soluble polymer is natural, semi-synthetic, synthetic, or
a combination thereof.
Embodiment 3
[0064] The particulate solid composition of embodiment 1 or 2,
comprising 10 to 90 weight percent of the dialkyl sulfosuccinate,
and 10 to 90 weight percent of the water-soluble polymer, based on
the total weight of the dialkyl sulfosuccinate and the
water-soluble polymer.
Embodiment 4
[0065] The particulate solid composition of any of embodiments 1-3,
consisting of the dialkyl sulfosuccinate and the water-soluble
polymer.
Embodiment 5
[0066] The particulate solid composition of any of embodiments 1-3,
further comprising 0 to 40 weight percent each, based on the total
weight of the particulate solid composition, of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals.
Embodiment 6
[0067] The particulate solid composition of any of embodiments 1-3,
wherein the particulate solid composition is free of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals.
Embodiment 7
[0068] The particulate solid composition of any of embodiments 1-3,
further comprising 0 to 5 weight percent of polysaccharides, sugar
alcohols, sodium benzoate, and sodium sulfate combined.
Embodiment 8
[0069] The particulate solid composition of any of embodiments 1-3,
wherein the particulate solid composition is free of sugar
alcohols, sodium benzoate, and sodium sulfate.
Embodiment 9
[0070] The particulate solid composition of any of embodiments 1-8,
wherein the particulate solid composition is free flowing.
Embodiment 10
[0071] The particulate solid composition of any of embodiments 1-9,
wherein the particulate solid composition has a distilled water
solubility of 1 to 20 weight percent at 23.degree. C., with no
haze.
Embodiment 11
[0072] The particulate solid composition of any of embodiments
1-10, wherein 3 parts by weight of the particulate solid
composition has a dissolution time in 87 parts by weight distilled
water at 23.degree. C. of less than 20 minutes.
Embodiment 12
[0073] The particulate solid composition of any of embodiments
1-11, wherein the dialkyl sulfosuccinate has the chemical
structure:
##STR00002##
wherein R.sup.1 and R.sup.2 are each independently a linear or
branched C.sub.4-18 alkyl, C.sub.5-18 cycloalkyl, C.sub.7-18
arylalkyl, or C.sub.6-18 aryl, unsubstituted or substituted by
hydroxyl or C.sub.1-18 alkoxy; and M is an alkali metal, an
alkaline earth metal, an ammonium ion, or a combination thereof,
and m is 0.5 when M is an alkaline earth metal, and m is 1 when M
is an alkali metal or ammonium ion.
Embodiment 13
[0074] The particulate solid composition of embodiment 12, wherein
R.sup.1 and R.sup.2 are both 2-ethylhexyl, M is sodium, and m is
1.
Embodiment 14
[0075] The particulate solid composition of any of embodiments
1-13, wherein the water-soluble polymer has a solubility of greater
than 0.1 gram per liter when dissolved in pH 1.2 hydrochloric acid
buffer for 40 minutes at 37.degree. C.
Embodiment 15
[0076] The particulate solid composition of any of embodiments
1-13, wherein the water-soluble polymer has a solubility of greater
than 0.1 gram per liter when dissolved in pH 6.8 phosphate buffer
for 40 minutes at 37.degree. C.
Embodiment 16
[0077] The particulate solid composition of any of embodiments
1-13, wherein the water-soluble polymer comprises a cellulose
ether, a polysaccharide, a polyvinyl alcohol homopolymer or
copolymer, a polyvinyl pyrrolidone homopolymer or copolymer, a
polyvinyl caprolactam polymer or copolymer, a poly(meth)acrylate, a
poly(alkylene oxide) graft copolymer, or a combination thereof.
Embodiment 17
[0078] The particulate solid composition of any of embodiments
1-13, wherein the water-soluble polymer comprises hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, poly(vinyl
pyrrolidone-co-vinyl acetate), polyvinyl alcohol, poly(vinyl
acetate-co-vinyl alcohol), poly(ethylene oxide-co-vinyl
acetate-co-vinyl caprolactam), or a combination thereof.
Embodiment 18
[0079] The particulate solid composition of any of embodiments 1-3,
consisting essentially of 10 to 70 weight percent sodium dioctyl
sulfosuccinate and 30 to 90 weight percent of a water-soluble
polymer comprising poly(vinyl pyrrolidone-co-vinyl acetate),
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or a
combination thereof, based on the total weight of the dioctyl
sodium sulfosuccinate and the water-soluble polymer.
Embodiment 19
[0080] The particulate solid composition of any of embodiments
1-18, comprising primary particles, wherein the primary particles
are spherical and have a diameter range from 1 to 50 micrometers,
as determined by scanning electron microscopy.
Embodiment 20
[0081] The particulate solid composition of embodiment 19, further
comprising aggregates of the primary particles, wherein the
aggregates have a diameter range from 0.1 to 2 millimeters, as
determined by optical microscopy.
Embodiment 21
[0082] The particulate solid composition of any of embodiments
1-18, comprising flakes.
Embodiment 22
[0083] The particulate solid composition of embodiment 21, wherein
the flakes have a thickness of 1 to 100 micrometers.
Embodiment 23
[0084] The particulate solid composition of any of embodiments
1-22, wherein the particulate solid composition is amorphous.
Embodiment 24
[0085] The particulate solid composition of any of embodiments
1-22, wherein the particulate solid composition comprises a blend
of crystalline dialkyl sulfosuccinate and amorphous or
semi-crystalline water-soluble polymer.
Embodiment 25
[0086] A method of making a particulate solid composition,
comprising: mixing a dialkyl sulfosuccinate and a water-soluble
polymer in a solvent to form a solution, and spray drying the
solution to form the particulate solid composition, wherein: the
particulate solid composition comprises primary particles having a
diameter range from 1 to 50 micrometers, as measured by scanning
electron microscopy; and comprises, based on the total weight of
the composition, 0 to less than 5 weight percent each of active
pharmaceutical ingredients, generics, biologics, biosimilars,
excipients, nutraceuticals, diagnostic agents, and agricultural
chemicals.
Embodiment 26
[0087] A particulate solid composition made by the method of
embodiment 25.
Embodiment 27
[0088] The particulate solid composition of embodiment 26, further
comprising aggregates of the primary particles, wherein the
aggregates have a diameter range from 0.1 to 2 millimeters, as
determined by optical microscopy.
Embodiment 28
[0089] A method of making a particulate solid composition,
comprising: mixing a dialkyl sulfosuccinate and a water-soluble
polymer in a solvent to form a solution; contacting the solution
with a heated surface; and removing the solvent to form the
particulate solid composition, wherein the particulate solid
composition comprises flakes, and comprises, based on the total
weight of the composition, 0 to less than 5 weight percent each of
active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals.
Embodiment 29
[0090] The method of embodiment 25 or 28, wherein the solvent
comprises 0 to 10 weight percent water and 90 to 100 weight percent
of a C.sub.1-4 alcohol, based on the total weight of the
solvent.
Embodiment 30
[0091] A particulate solid composition made by the method of
embodiment 28 or 29.
Embodiment 31
[0092] The particulate solid composition of embodiment 30,
comprising flakes having a thickness of 1 to 100 micrometers, as
determined by scanning electron microscopy.
Embodiment 32
[0093] A method of making a water-soluble composition, comprising
mixing a particulate solid composition and an organic substance
having low water solubility, in amounts effective to form the
water-soluble composition; wherein: the particulate solid
composition comprises a blend of dialkyl sulfosuccinate, a
water-soluble polymer, and 0 to less than 5 weight percent each of
active pharmaceutical ingredients, generics, biologics,
biosimilars, excipients, nutraceuticals, diagnostic agents, and
agricultural chemicals, based on the total weight of the
water-soluble composition; the particulate solid composition has a
distilled water solubility of 1 to 20 weight percent at 23.degree.
C., with no haze; and the organic substance has a water solubility
of less than 1 weight percent at 23.degree. C.
Embodiment 33
[0094] The method of embodiment 32, wherein the organic substance
comprises an active pharmaceutical ingredient, a generic, a
biologic, a biosimilar, an excipient, a nutraceutical, a medical
diagnostic agent, an agricultural chemical, or a combination
thereof.
Embodiment 34
[0095] The particulate solid composition of any of embodiments
1-24, 26-27, and 30-31, wherein individual particles comprise both
the dialkyl sulfosuccinate and the water-soluble polymer.
[0096] This invention is further illustrated by the following
non-limiting examples.
Examples
[0097] The materials utilized in the examples are described below
in Table 1.
TABLE-US-00001 TABLE 1 Materials Abbreviation Description DOSS
Sodium dioctyl sulfosuccinate, C.A.S. Reg. No. 577-11-7, in
granular form, available from Solvay S.A., also known as sodium
docusate, or docusate. DOSS-70 70% Solution of sodium dioctyl
sulfosuccinate, C.A.S. Reg. No. 577-11-7, in 23A specially
denatured ethanol, available from Solvay S.A. SB Sodium benzoate,
C.A.S. Reg. No. 532-32-1, available from Sigma Aldrich. DOSS-SB
DOSS-SB, 85:15 by weight, C.A.S. Reg. No. 511-11-7, available as
DSS Granular from Solvay S.A. D-Mannitol
(2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol, C.A.S. Reg. No. 69-65-8,
available from Harke Group. SOLUPLUS .TM. Poly(ethylene
glycol-vinyl acetate-N-vinyl caprolactam) graft copolymer, C.A.S.
Reg. No. 02932-23-4, available from BASF. HPMC
2-Hydroxylpropylmethyl cellulose, C.A.S. Reg. No. 5004-65-3, having
a viscosity of 2.4-3.6 mPa s, available as PHARMACOAT .TM. 603 from
Shin-Etsu Chemical. Copovidone Poly(N-vinyl pyrrolidone-co-vinyl
acetate), from 6:4 by weight N- vinylpyrollidone:vinyl acetate,
C.A.S. Reg. No. 25086-89-9, available as KOLLIDON .TM. VA 64, from
BASF. EPO Poly(butyl methacrylate-co-(2-dimethylaminoethyl)
methacrylate- co-methyl methacrylate), 1:2:1, C.A.S. Reg. No.
24938-16-7, available from Evonik Industries as EUDRAGIT .TM. E PO.
SLS Sodium lauryl sulfate, C.A.S. Reg. No. 151-21-3. TWEEN .TM. 80
Polyoxyethylene (20) sorbitan monooleate, available from Croda.
TWEEN .TM. 20 Polyoxyethylene (20) sorbitan monolaurate, available
from Croda. Ibuprofen (RS)-2-(4-(2-Methylpropyl)phenyl)propanoic
acid, C.A.S. Reg. No. 15687-27-1. Fenofibrate Propan-2-yl
2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2- methylpropanoate, C.A.S.
Reg. No. 49562-28-9. Naproxen (+)-(S)-2-(6-methoxynaphthalen-2-yl)
propanoic acid, C.A.S. Reg. No. 22204-53-1. Ritonavir
1,3-Thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-
methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-
yl]methyl})carbamoyl]amino}butanamido]-1,6-
diphenylhexan-2-yl]carbamate, C.A.S. Reg. No. 155213-67-5.
Glipizide N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-5-
methylpyrazine-2-carboxamide, C.A.S. Reg. No. 29094-61-9.
Examples 1-5
[0098] DOSS and water-soluble polymer in the amounts provided in
Table 2 were dissolved in 50 parts distilled water with gentle
mixing to form solutions. The solutions were spray dried using the
following conditions: Buchi B-150 Spray dryer with cyclone
technology, inlet temperature of 100.degree. C., outlet temperature
of 35.degree. C., and a flow rate of 25 g/hr.
TABLE-US-00002 TABLE 2 Spray Dry Solution Compositions Amount Exam-
Exam- Exam- Exam- Exam- (parts by weight) ple 1 ple 2 ple 3 ple 4
ple 5 DOSS 3.33 3.33 3.33 3.33 3.33 SOLUPLUS .TM. 6.67 7.00 -- --
-- HPMC -- -- 6.67 -- -- Copovidone -- -- -- 3.33 6.67 Mannitol --
-- -- 3.33 -- Distilled water 50 50 50 50 50
Best results were obtained in Examples 3 and 5, in which yields of
up to 75% were obtained. In Example 3, there was no precipitation
of the DOSS blends in the spray-drier, and therefore no deposits or
clogging of the lines.
Comparative Example 1
[0099] Comparative Example 1 is DOSS and SB in an 85:15 weight
ratio, C.A.S. Reg. No. 511-11-7, available as DSS Granular from
Solvay S.A.
Examples 6-8 and Comparative Example 2
[0100] In Comparative Example 2, an attempt was made to prepare
DOSS-copovidone by vacuum drum drying as follows. DOSS and
copovidone in a 3:1 weight ratio were dissolved in sufficient water
to form a 24 wt. % solids solution. A 6'' wide.times.8'' long
vacuum double drum dryer having steam heated 5/16'' thick chrome
plated cast iron drums and 2.00 ft.sup.2 dryer surface area was
used. Phenolic fiber endboard were used to contain the solution
between the drums. A tempered tool steel scraper knife was located
at the outer horizontal quadrant of each drum. The scraper knife
makes contact with the drum surfaces to remove the dried product.
The solution was fed between the drums from the top using a glass
separatory funnel under a vacuum of 34 mm Hg. The solution was
added under a vacuum of 34 mm Hg, and the solution temperature at
the scraper knives was 132.degree. C. However it was not possible
to obtain dry DOSS-copovidone under these conditions. The product
remained molten at the temperature required to evaporate the water
(132.degree. C.), and therefore could not captured by the scraper
knives.
[0101] Surprisingly, it was found that DOSS-copovidone could be
prepared by vacuum drum drying in the same apparatus when the
components are dissolved in ethanol rather than water as follows.
In Comparative Example 6, DOSS and copovidone in a 1:2 weight ratio
were dissolved in denatured ethanol to form a 52.2 wt. % solids
solution. The solution was fed between the drums from the top under
a vacuum of 55 mm Hg. The product had assays of 32.8 wt. % DOSS and
67.3 wt. % copovidone, and a water content of 1.6 wt. %.
[0102] The process of Example 6 was readily scalable. In Example 7,
100 lbs. of DOSS-copovidone were prepared at 711 mm Hg using A
12''.times.18'' vacuum double drum dryer having a 5/16'' thick
chrome plated cast iron drum and 9.4 ft.sup.2 dryer surface area
inside a steam-traced, stainless steel vacuum enclosure. Hot water
at 60-80.degree. C. was used for heating. The dried DOSS-copovidone
formed intact sheet rolls when cut from the drum. Upon cooling, the
rolls were brittle and readily milled into a powder using a cone
mill. The product had DOSS and copovidone assays of 35.5 and 64.6
wt. %, respectively, and a water content of 1.6 wt. %. In Example
8, the DOSS-copovidone of Example 7 was further dried at 65.degree.
C. under vacuum for two days.
[0103] Surprisingly, the physical form of DOSS-copovidone of
Examples 7 and 8 is thin flakes. SEM photographs are provided for
Example 8 in FIG. 11-13 at magnifications of 250.times.,
500.times., and 1000.times., respectively. These images are not
representative of size distribution as some larger particles did
not fit into field of view. Flake thickness ranges from about 1 to
about 10 micrometers.
Example 9
[0104] A sample of DOSS-HPMC was prepared by spray drying as
follows. PHARMACOAT.TM. 603 (71.2 lb., 32.3 kg) and DOSS-70 were
dissolved in 581.8 lb. (263.9 kg) of USP deionized water at 100 to
110.degree. F. (37.8 to 43.3.degree. C.) to form an about 15 wt. %
solids solution. The PHARMACOAT.TM. 603 was added slowly with high
shear mixing. The resulting solution was spray dried at a inlet air
temperature of 365 to 385.degree. F. (185 to 196.degree. C.), an
outlet air temperature of 150 to 200.degree. F. (65.6 to
93.3.degree. C.). The dried product was put through a 20 Mesh HACCP
Sifter Screen.
Characterization
[0105] The blends of Examples 3 and 5 and Comparative Example 1
(DSS Granular) were characterized. The results are reported in
Table 3.
TABLE-US-00003 TABLE 3 Characterization of Dioctyl Sulfosuccinate
Blends Exam- Exam- Comp. Components ple 3 ple 5 Ex. 1 DOSS (wt. %)
32.8 32.9 84.5 Water (wt. %) 3.7 4.8 0.7 HPMC (wt. %) ca. 63.sup.a
-- -- Copovidone (wt. %) -- ca. 62.sup.a -- SB (wt. %) -- -- 14.8
Appearance White White White powder powder powder Particle Size
(micrometers) 2-15 2-15 >100 Bulk Density at 25.degree. C.
(kg/m.sup.3) 0.27 0.29 0.37 Surface Tension at CMC 29 28 26 at
25.degree. C. (mN/m) CMC (wt. %) 0.29 0.13 0.12 BET Surface Area
(m.sup.2/g) 1.6592 0.7180 2.2091 Single Point Surface Area
(m.sup.2/g) 1.2495 0.5758 1.1758 Conc. in Water (g/L) Solubility at
23.degree. C., (NTU)/Appearance 10 1.0, clear 0.9, clear 322, hazy
30 1.6, clear 1.8, clear 360, hazy 50 2.8, clear 3.7, clear 567,
hazy 100 266, clear 8.3, clear 550, hazy .sup.aEstimated from DOSS
and water amounts by difference.
[0106] DOSS was assayed by titration with HYAMINE.TM. 1622. Water
was determined by Karl Fischer titration. HMPC and copovidone
contents were estimated from DOSS and water amounts by difference.
Sodium benzoate was assayed by titration with tetra-n-butylammonium
iodide. Photographs of DOSS (right), HPMC (center), and the
DOS-HPMC blend of Example 3 (left) are reproduced in FIG. 1, and
photographs of DOSS (right), copovidone (center), and the
DOSS-copovidone blend of Example 5 are reproduced in FIG. 2. DOSS
is in the form of sticky, waxy flakes. Advantageously, the
DOSS-HPMC and DOSS-copovidone blends are free flowing, fine
powders. The DOSS-HPMC and DOSS-copovidone blends have lower bulk
density than both DOSS alone and DOSS-SB complex. In particular, as
can be seen from Table 3, while DOSS-SB has a bulk density of 0.37
kg/m.sup.3, DOSS-HMPC and DOSS-copovidone have bulk densities of
0.27 and 0.29 kg/m.sup.3, respectively.
[0107] Particle size was determined by scanning electron microscopy
(SEM). Images were acquired using a Zeiss Sigma VP SEM using the
SE-detector at 1 KeV. FIG. 3a, FIG. 3b, and FIG. 3c depict SEM
photographs of the DOSS-HPMC of Example 3 at magnifications of
500.times., 3,000.times. and 5,000.times., respectively. FIG. 4a,
FIG. 4b, and FIG. 4c depict SEM photographs of the DOSS-copovidone
of Example 3 at magnifications of 1,000.times., 2,000.times. and
5,000.times., respectively. FIG. 5a, FIG. 5b, and FIG. 5c depict
SEM photographs of the DOSS-SB of Comparative Example 1 at
magnifications of 200.times., 500.times. and 1,000.times.,
respectively. As can be seen from the SEM photographs, the
DOSS-HPMC and DOSS-copovidone particles are spherical, while the
DOSS-SB particles are irregularly-shaped. HPMC particles were
macroscopic and irregularly-shaped. Advantageously, DOSS-HPMC and
DOSS-copovidone have volume particle diameter ranges of 2 to 15
micrometers, while the DOSS-SB blend has a volume particle diameter
range of about 100 micrometers and above, as determined by SEM.
Surface Area
[0108] Surface area is a measure of the exposed surface of a solid
sample on a molecular scale. BET surface area was measured
according to the Brunauer, Emmet and Teller model. Test samples
were prepared by simultaneous heating and evacuating or flowing gas
over the sample to remove vaporized impurities. The prepared
samples were then cooled with liquid nitrogen and analyzed by
measuring the volume of krypton gas absorbed at specific
pressures.
Surface Tension
[0109] The surface tensions of solutions of Examples 3 (DOSS-HPMC)
and 5 (DOSS-copovidone, and Comparative Example 1 (DOSS) were
measured at different concentrations in distilled water. The
results are plotted in FIG. 6. Critical micelle concentration (CMC)
and surface tension at the CMC are provided in Table 3. As can be
seen from Table 3, the CMC, and the surface tension at CMC, for the
DOSS-HPMC and DOSS-copovidone blends are comparable to the CMC and
surface tension at CMC for DOSS. Thus, the water-soluble polymers
are expected to have little or no impact on the surface activity of
DOSS, and its efficacy as a surfactant.
Water Solubility
[0110] DOSS, USP grade, is available as solid white waxy rolls. It
has a solubility in water of only about 1 in 70 parts per R. C.
Rowe, P. J, Sheskey, M. E. Quinn (Ed.), Handbook of Pharmaceutical
Excipients, 6th ed. pp. 244-246. This corresponds to a solubility
of 15 g/L. DOSS-SB, available as DSS Granular, has comparable water
solubility. Surprisingly DSS provided as DOSS-copovidone and
DOSS-HPMC provide stable supersaturated solutions of DOSS. Water
solubility is defined herein as a concentration of dioctyl
sulfosuccinate blend that provides a clear solution in water, i.e.
has a turbidity of less than 200 Nephelometric Turbidity Units
(NTU's). Turbidity was measured using a nephelometer with the
detector set up to the side of the light beam. As can be seen from
Table 3, DOSS-HPMC provides clear solutions up to at least 50 g/L
DOSS, the actual water solubility being between 50 to 100 g/L.
DOSS-copovidone provides clear solutions up to at least 100 g/L,
indicated a water solubility exceeding 100 g/L. In contrast, the
DOSS-SB blend is insoluble, even at 10 g/L, providing a hazy
solution having a turbidity of 322 NTU's. These data show that
surprisingly, DOSS-HPMC and DOSS-copovidone provide stable
supersaturated solutions of DOSS in water.
Powder X-Ray Diffraction (PXRD)
[0111] Approximately 1 gram of the sample was placed on a standard
aluminum holder and was used for X-ray diffraction (XRD) on a
Rigaku Multiflex X-ray diffractometer using a Cu K.alpha. radiation
source (.lamda.=0.1541 nm) at 40 kV and 20 mA. The data was
collected between the scan range of 5-60.degree. 20 and a step size
of 0.02.degree.. The diffractograms were analyzed by Jade software
version 9.0, with reference patterns from the Powder Diffraction
File 4 (PDF-4) database licensed by the International Center for
Diffraction Data (ICDD).
[0112] FIG. 7 depicts individual powder X-ray diffraction (PXRD)
patterns for DOSS and copovidone, overlaid. (Sodium docusate is
another name for DOSS.) The sharp peak at a scattering angle (2
theta) of about 4.degree. for DOSS is indicative of a crystalline
morphology. The broad peaks for copovidone are indicative of an
amorphous or semi-crystalline morphology. FIG. 8 depicts the PXRD
pattern for DOSS-copovidone (Docusate is another name for DOSS, and
XSM-2414 is a code for DOSS-copovidone). The sharp peak at a
scattering angle of about 4.degree. and the broad peak at a
scattering angle of about 21.degree. indicate the presence of both
crystalline DOSS and amorphous or semi-crystalline copovidone in
the DOSS-copovidone blend.
[0113] FIG. 9 depicts individual PXRD patterns for DOSS and HPMC,
overlaid. (Sodium docusate is another name for DOSS.) The broad
peaks for HPMC are indicative of an amorphous or semi-crystalline
morphology. FIG. 10 depicts the powder X-ray diffraction pattern
for DOSS-HPMC prepared by vacuum drum drying. (Docusate is another
name for DOSS, and XSM-2214 is a code for DOSS-HPMC) As with the
PXRD pattern for DOSS-copovidone, the sharp peak at a scattering
angle of about 4.degree. and the broad peak at a scattering angle
of about 19.degree. indicate the presence of both crystalline DOSS
and amorphous or semi-crystalline HPMC in the DOSS-HPMC blend.
Contact Angle
[0114] A factor which contributes to the bioavailability of active
pharmaceutical ingredients (API's) is the wetting of the API by an
aqueous solution at a physiological pH. Wetting can affect
dissolution rates of the API in the aqueous solution. Wetting can
be assessed by measuring the contact angle between an aqueous
solution and an API. In these examples, the sessile drop method was
used to determine contact angles. Pellets of API were produced
using an X-press 3630 with a 35-mm pressing die. The API was
pressed into a 35-mm diameter aluminum pan using the standard
30-ton cycle in order to produce a flat surface. Drops (10-.mu.L)
of a 0.1% test solution of an excipient were used. The test
solution was 0.1 M HCl, to simulate physiological conditions in the
human stomach. As can be seen from Table 4, contact angles of less
than 5.degree. were obtained for ibuprofen, fenofibrate, naproxen
and glipizide when the excipient was DOSS, regardless of the
physical form of DOSS used, be it DOSS, DOSS-SB, DOSS-HPMC, or
DOSS-copovidone. These data show that the presence of HPMC or
copovidone does not adversely affect the advantageous effect DOSS
has on contact angles with the API's.
TABLE-US-00004 TABLE 4 Contact Angle of Excipient Solutions in 0.1M
HCl with API's Contact Angle (.degree.) Ibupro- Feno- Naprox- Rito-
Glipi- Excipient fen fibrate en navir zide DOSS-HPMC <5 <5
<5 23 <5 DOSS-copovidone <5 <5 <5 25 <5 DOSS
<5 <5 <5 20 <5 DOSS-SB <5 <5 <5 33 <5 SLS
54 47 34 57 43 TWEEN .TM. 20 45 58 48 40 42 TWEEN .TM. 80 68 70 52
51 55
Dissolution Time
[0115] Dissolution times for DOSS, DOSS-SB, HPMC, copovidone,
DOSS-HPMC, and DOSS-copovidone were measured as follows. The
excipient (3 parts by weight) was added to 87 parts by weight of
deionized water at 23.degree. C. with mechanical stirring. Stirring
was interrupted approximately every minute for less than 10 seconds
to make a visual observation. The results are summarized in Table
5. Dissolution of DOSS, which is supplied in granular form, in
water was difficult, taking about 40 minutes to dissolve.
Dissolution time was improved by the addition of sodium benzoate to
the DOSS, but was still about 20 minutes for the DOSS-SB.
Advantageously, the present particulate solid compositions,
DOSS-HPMC and DOSS-copovidone, dissolve in water faster than DOSS
alone, and also faster than DOSS-SB blends. As can be seen from
Table 6, while DOSS, dissolved in 37 minutes, the DOSS-HPMC of
Example 3 dissolved in only 10 minutes. Moreover, while DOSS
dissolved in 41:20 in a separate experiment, the DOSS-copovidone of
Example 5 dissolved in only 3:30.
TABLE-US-00005 TABLE 5 Dissolution Times in Deionized Water
Dissolution Material Time (min.) DOSS 37 HPMC 16 DOSS Time + HPMC
Time 53 DOSS-HPMC (Ex. 3) 10 DOSS 41 Copovidone 4 DOSS-copovidone
(Ex. 5) 3-4 DOSS-SB 20
[0116] Further water dissolution studies were carried out on the
DOSS-copovidone of Examples 7 and 8, and the DOSS-HPMC of Example
9. This time, 2.000.+-.0.0200 g excipient was dissolved in 200 g of
deionized water, or 200 g of 0.1 M HCl. Dissolution rates in both
deionized water and 0.1 M hydrochloric acid (to model human stomach
conditions) were evaluated. The results are summarized below in
Table 6. As can be seen from the table, dissolution times in 0.1 M
HCl were comparable to dissolution times in deionized water,
although DOSS-HPMC was somewhat slower to dissolve in 0.1 M
HCl.
TABLE-US-00006 TABLE 6 Dissolution Times in Deionized Water and
0.1M HCl Dissolution Time (min) Example 7 8 9 Type DOSS- DOSS-
DOSS- copovidone copovidone HPMC Deionized water 3 4 7 0.1M HCl 3.5
4 10
Fourier Transform Infrared Imaging of DOSS-HPMC
[0117] Fourier Transform infrared (FTIR) measurements and imaging
were made on an Agilent Technologies Cary 600 Series FTIR imaging
system at a resolution of 4 cm.sup.-1 by averaging 64 scans and
using Resolutions Pro software (version 5.2.0, Agilent). All three
available modes of measurement were employed--reflection mode,
attenuated total reflection (ATR) mode, and transmission mode
(transmitted reflection, or transflection). In reflection mode
chemical composition information was obtained from the sample
surface by analyzing diffusely scattered and specularly reflected
IR radiation. In ATR mode, chemical composition information was
obtained from the sample surface by analyzing evanescent wave
phenomena. In transmission mode, chemical composition information
was obtained from the bulk of the sample. For reflection and
transmitted reflection modes, a gold coated mirror was used as a
reference. Also for the transmitted reflection mode, the samples
were compressed in a diamond compression cell. In some of the FTIR
imaging, particles on the high end of the particle size
distribution were utilized, due to limitations in resolution of the
methods.
[0118] Samples (1) and (2) of DOSS-HPMC showing individual
particles and particle aggregates were placed on a gold-coated
mirror, and analyzed by visible micrography and FTIR. The results
are depicted in FIG. 14. The results for Sample (1) are presented
in FIGS. 14-1 to 14-3; and the results for Sample (2) are presented
in FIGS. 14-4 to 14-6. Visible micrographs of Samples (1) and (2)
are in FIGS. 14-1 and 14-4, respectively. Two-dimensional FTIR
vibrational images of Samples (1) and (2), measured in reflectance
mode, are in FIGS. 14-2 and 14-3, and in FIGS. 14-5 and 14-6,
respectively. The field of view for both samples was 350.times.350
.mu.m. The exact spatial resolution was dependent on the analytical
wavelength used to generate the images. However it was generally
approximately 5 .mu.m. Analytical wavelengths of 1735 cm.sup.-1 for
DOSS and 1064 cm.sup.-1 for HPMC were selected based on the
overlaid one-dimensional FTIR spectra of DOSS and HPMC in FIG.
14-9. FIGS. 14-2 and 14-5 are DOSS-specific images, based on
absorption at 1735 cm.sup.-1, and FIGS. 14-3 and 14-6 are
HPMC-specific images, based on absorption at 1064 cm.sup.-1. The
data for Sample (1) were further converted into the
three-dimensional DOSS- and HPMC-specific images of FIGS. 14-7 and
14-8, respectively. As can be seen from comparing the visible
micrographs and the FTIR vibrational images, at a resolution of
approximately 5 .mu.m, each particle contains both DOSS and HPMC.
Thus, the DOSS-HPMC is not merely a physical mixture of individual
DOSS and HPMC particles. Instead, it is an intimate blend of DOSS
and HPMC.
[0119] A sample of DOSS-HPMC particles of different sizes was
analyzed by FTIR attenuated total reflectance (ATR) imaging. ATR
was utilized, because it provides an approximately 4-fold
improvement in spatial resolution as compared to reflection or
transmission imaging. The results are depicted in FIG. 15. The
field of view was 70.times.70 .mu.m. The imaging was conducted to a
depth of approximately 1 .mu.m from the particle surface, and at a
spatial resolution of approximately 1 .mu.m. FIG. 15-1 is a
DOSS-specific image and FIG. 15-2 is an HPMC-specific image. A
25.times.47 .mu.m portion of the HPMC-specific image was normalized
for HPMC content, and the DOSS content at normalized HPMC content
is depicted in FIG. 15-3. The normalized FTIR image on the right
was generated by normalizing the absorbance at 1064 cm.sup.-1, the
analytical wavelength for HPMC, to 1.0 for every pixel, and
displaying the resulting normalized absorbance at 1735 cm.sup.-1,
which is the analytical wavelength for DOSS. As can be seen from
FIG. 15-3, the ratio of DOSS to HPMC is not constant, which
indicates that there are domains of varying ratios of DOSS and HPMC
for the surface layer to a depth of approximately 1 .mu.m and at a
spatial resolution of approximately 1 .mu.m.
[0120] A sample of DOSS-HPMC showing individual particles and
particle aggregates was flattened in a diamond compression cell and
analyzed by visible micrography and FTIR imaging. The results are
depicted in FIG. 16. The field of view was 350.times.350 .mu.m. The
exact spatial resolution was dependent on the analytical wavelength
used to generate the images. However it was generally approximately
5 .mu.m. A visible micrograph is in FIG. 16-1, and FTIR vibrational
images, measured in transmission mode, are in FIGS. 16-2 and 16-3.
Analytical wavelengths of 1735 cm.sup.-1 for DOSS and 1064
cm.sup.-1 for HPMC were selected based on the overlaid FTIR spectra
of DOSS and HPMC in FIG. 14-9. FIG. 16-2 is a DOSS-specific image,
based on absorption at 1735 cm.sup.-1, and FIG. 16-3 is an
HPMC-specific image, based on absorption at 1064 cm.sup.-1. A
110.times.110 .mu.m portion of the HPMC-specific image was
normalized for HPMC content, and the DOSS absorbance at normalized
HPMC absorbance is depicted in FIG. 16-4. The normalized IR image
was generated by normalizing the absorbance at 1064 cm.sup.-1, the
analytical wavelength for HPMC, to 1.0 for every pixel, and
displaying the resulting normalized absorbance at 1735 cm.sup.-1,
which is the analytical wavelength for DOSS. As can be seen from
FIG. 16-4, the ratio of DOSS to HPMC is again not constant, which
again indicates that there are domains of varying ratios of DOSS
and HPMC throughout the bulk of the sample.
Fourier Transform Infrared Imaging of DOSS-Copovidone
[0121] A sample of DOSS-copovidone particle aggregates was
flattened in a diamond compression cell and analyzed by visible
micrography and FTIR imaging. The results are depicted in FIG. 17.
The field of view was 350.times.350 .mu.m. The exact spatial
resolution was dependent on the analytical wavelength used to
generate the images. However it was generally approximately 5
.mu.m. A visible micrograph is in FIG. 17-5, and FTIR vibrational
images, measured in transmission mode, are in FIGS. 17-1 and 17-2.
Analytical wavelengths of 2958 and 2874 cm.sup.-1 for DOSS (FIGS.
17-1 and 17-2, respectively) and 1494 cm.sup.-1 for copovidone
(FIG. 17-3) were selected based on the overlaid IR spectra of DOSS
and copovidone in FIG. 17-4. FIGS. 17-1 and 17-2 are DOSS-specific
images, based on the absorptions at of 2958 and 2874 cm.sup.-1,
respectively, and FIG. 17-3 is a copovidone-specific image, based
on the absorption at 1494 cm.sup.-1. FIG. 17-6 is a
three-dimensional representation of the two-dimensional copovidone
image of FIG. 17-3. As can be seen from the FTIR images, at a
resolution of approximately 5 .mu.m, each pixel of the sample
contains both DOSS and copovidone. Thus the DOSS-copovidone is not
merely a physical mixture of individual DOSS and copovidone
particles. Instead, it is an intimate blend of DOSS and copovidone
through the bulk of the sample.
[0122] A sample of DOSS-copovidone was compressed into a flat
pellet using a diamond compression cell, and analyzed by visible
micrography and FTIR imaging. The results are depicted in FIG. 18.
A visible micrograph is in FIG. 18-1, and FTIR vibrational images,
measured in transmission mode, are in FIGS. 18-2 and 18-4. The
exact spatial resolution was dependent on the analytical wavelength
used to generate the images. However it was generally approximately
5 .mu.m. FIG. 18-2 is a DOSS-specific image, based on the
absorption at 2874 cm.sup.-1, and FIG. 18-4 is a
copovidone-specific image, based on the absorption at 1494
cm.sup.-1. FIG. 18-3 is a three-dimensional representation of the
two-dimensional DOSS image of FIG. 18-2, and FIG. 18-5 is a
three-dimensional representation of the two-dimensional copovidone
image of FIG. 18-4. As can be seen from the FTIR images, at a
resolution of approximately 5 .mu.m, each pixel of the sample
contains both DOSS and copovidone. This is further evidence that
DOSS-copovidone is not merely a physical mixture of individual DOSS
and copovidone particles. Instead, it is an intimate blend of DOSS
and copovidone.
[0123] As used herein, "polymers" refers to homopolymers and
copolymers, unless specified otherwise.
[0124] When a composition is described as "free of" a given
material, this indicates that there is no measurable amount of the
material in the composition.
[0125] Unless specified otherwise, solubility is expressed in units
of weight percent, and the units of weight percent are based on the
total weight of the solute and solvent.
[0126] As used herein, the construction, "DOSS-water soluble
polymer", for example "DOSS-HPMC" and "DOSS-copovidone", refers to
the particulate solid composition made by methods disclosed herein,
wherein individual particles of the particulate solid contains both
DOSS and the water-soluble polymer. Thus, it refers to an intimate
mixture of DOSS and water-soluble polymer, rather than a physical
mixture of DOSS particles and water-soluble polymer particles.
Thus, "DOSS-water soluble polymer" can also be referred to as a
DOSS-water soluble blend, for example a DOSS-HPMC blend or
DOSS-copovidone blend.
[0127] As used herein, the terms "a" and "an" do not denote a
limitation of quantity, but rather the presence of at least one of
the referenced items. Recitation of ranges of values are merely
intended to serve as a shorthand method of referring individually
to each separate value falling within the range, and each separate
value is incorporated into this specification as if it were
individually recited. Thus each range disclosed herein constitutes
a disclosure of any sub-range falling within the disclosed range.
Disclosure of a narrower range or more specific group in addition
to a broader range or larger group is not a disclaimer of the
broader range or larger group. All ranges disclosed herein are
inclusive of the endpoints, and the endpoints are independently
combinable with each other. "Comprises" as used herein includes
embodiments "consisting essentially of" or "consisting of" the
listed elements.
[0128] While typical embodiments have been set forth for the
purpose of illustration, the foregoing descriptions should not be
deemed to be a limitation on the scope herein. Accordingly, various
modifications, adaptations, and alternatives can occur to one
skilled in the art without departing from the spirit and scope
herein.
* * * * *