Composition for pH dependent controlled release of active ingredients and methods for producing it

The present invention is related to a composition for pH dependent or pH regulated controlled release of active ingredients especially drugs. The composition consists of a compactible mixture of the active ingredient and starch molecules substituted with acetate and dicarboxylate residues. The preferred dicarboxylate acid is succinate. The average substitution degree of the acetate residue is at least 1 and 0.2-1.2 for the dicarboxylate residue. The starch molecules can have the acetate and dicarboxylate residues attached to the same starch molecule backbone or attached to separate starch molecule backbones. The present invention also discloses methods for preparing said starch acetate dicarboxylates by transesterification or mixing of starch acetates and starch dicarboxylates respectively.

THE BACKGROUND OF THE INVENTION 
1. The Technical Field of the Invention 
The present invention is related to compositions for pH dependent 
controlled release of active ingredients, especially pharmaceutical 
compositions. The composition is a compact consisting essentially of an 
active ingredient and a starch acetate dicarboxylate such as succinate. 
Methods for preparing the composition are also disclosed. 
2. The Background of the Invention 
Active compounds such as pharmaceuticals, natural health products, 
fertilizers, herbicides, insecticides, diagnostic reagents are usually not 
distributed as such, but in the form of more convenient compositions which 
make the distribution more feasible and allows the preparation of 
convenient dosage forms for different environmental conditions. Among 
these environmental conditions the acidity of the environment is an 
important factor. Pharmaceutical preparations are perhaps the most 
thoroughly studied compositions. Thus, the background for designing the 
present pH dependent controlled release compositions is discussed in more 
detail fundamentally based on the knowledge accumulated in studies with 
pharmaceutical preparations. 
Pharmaceutical preparations typically comprise one or several excipients in 
addition to the active drug substance or substances. Excipients make the 
manufacturing of the pharmaceutical dosage forms more feasible and give 
them suitable physicochemical, biological and biopharmaceutical 
properties. 
The administration of drugs to the human or animal body by way of 
controlled, sustained or delayed release from a dosage form located in 
gastrointestinal tract has long been an objective of the pharmaceutical 
industry. The controlled release dosage forms are used to optimize drug 
therapy, decrease frequency of dosing, and minimize undesirable side 
effects. It is generally known that the residence time of a drug in the 
stomach is largely unpredictable and it depends on the physiology of the 
individual and the amount and type of food which is taken with a meal. 
Thus, variations between different patients are particularly significant. 
On the other hand, the pH conditions in stomach and small intestine are 
markedly different. Numerous drugs are slightly soluble in acidic 
environment of stomach and they can be absorbed only when the surrounding 
pH is greater than 5, as it is in small intestine. Sustained or delayed 
release properties in dosage forms are primarily intended to extend the 
release of drug over an prolonged period of time to maintain therapeutic 
effective blood levels or to decrease the risks of side-effects. In 
addition, they are used to control the release of a drug at a 
predetermined point or predetermined points in the gastrointestinal tract. 
One among these effects is the enteric effect. 
By definition, enteric dosage forms are those which remain practically 
intact in the stomach, but will disintegrate or dissolve and release the 
drug contents once the product reaches the small intestine. Their prime 
intention is to delay the release of drugs which are inactivated by the 
stomach contents, or may cause nausea or bleeding by irritation of the 
gastric mucosa, or are more preferentially absorbed into blood circulation 
from small intestine, or have local therapeutic effect in small intestine. 
The most widely used technology for obtaining enteric effect is the coating 
of a compressed tablet by a polymeric film with enteric properties. The 
powder mixture consisting of drug substance(s) and several excipients is, 
firstly, mixed, most often also granulated and then compressed into 
tablets. These tablets are then coated in film coating processes. The 
preparation of coated products is a multistage process, including several 
separate mixing, granulation, tabletting and coating phases with numerous 
and complicated process variables. 
Systems based on pH-sensitive polymers tend to be more reliable than those 
which are dependent of slow dissolution and erosion of the polymer. The 
most extensively used enteric polymer is cellulose acetate phthalate. 
Cellulose acetate phthalate films have good enteric properties, but they 
dissolve only over pH 6 and may thus delay drug release longer than 
desired. Said cellulose acetate phthalate films are also susceptible to 
hydrolytic breakdown on storage. Other enteric polymers include e.g. 
polyvinylacetate phthalate, hydroxy-propylmethylcellulose phthalate, 
methacrylic acid-methacrylic acid ester copolymer, starch and amylose 
acetate phthalate, styrene maleic acid copolymer, and cellulose acetate 
succinate. 
The enteric coatings are typically prepared by using either fludized bed or 
pan coating techniques. The application of enteric polymers is often 
accomplished by spraying organic solvent based solutions containing from 5 
to 30% polymer. Although, water is the solvent of choice in pharmaceutical 
processes, even nowadays organic solvents are most often used in enteric 
coating processes. The evaporation of solvents and their possible harmful 
effects on tablet structure may, however, restrict the usability of the 
coating technique. Often plasticizers or some other components are mixed 
into the coating solution to improve film quality. Typical problems of 
enteric coating include tackiness, too porous structure or cracking of the 
films. Naturally, also all the other problems occasionally occurring in 
conventional film coating processes may exist in enteric coatings. The 
controlling and repeatability of the whole manufacturing chain is 
especially complicated. Often difficulties may arise due to breaking or 
inhomogeneity of a thin enteric coating film. As a consequence, the drug 
content can be released earlier than desired. 
It is also known to prepare controlled release preparations by compressing 
formulations containing matrix forming excipients. Due to poor flowing, 
stickiness and smeary properties of enteric coating polymers, this method 
is very seldom used for preparation of enteric formulations. Direct 
compression of these substances without granulation in manufacturing scale 
is hardly possible. 
Polymeric matrix formers with enteric properties, which can be processed by 
compressing, would be important in respect to time and energy saving as 
well as to better controlling of the whole manufacturing chain. The 
manufacture of enteric formulations using a compression process is in 
principle a simple and easily controllable process. If the direct 
compression process without granulation as a preprocess can be performed, 
it is possible to design even more simplified and better controllable 
manufacturing processes. Several disadvantageous process factors, e.g. 
granulation, drying of granules, usage of organic solvents, can then be 
avoided. 
In patent application PCT/FI95/00331 corresponding to U.S. patent 
application Ser. No. 08/374,430 filed Jan. 19, 1995, claiming priority 
from the Finnish patent application Ser. No. 942686 filed on Jun. 7, 1994, 
a composition comprising compacts of starch acetates and active 
ingredients is disclosed. Said composition is characterized by its 
modifiable properties. In said patent application PCT/FI95/00331 it is 
also disclosed how to make different kinds of compacts, which are best 
suited for a certain purpose, e.g. controlled or sustained release. The 
release of the active ingredient from said composition is however not pH 
dependent. 
As described above there is especially a need of pharmaceutical pH 
dependent controlled release compositions or entero-compositions such as 
compacts, e.g. tablets, granules and pellets. Even if the need for such a 
composition is especially prominent for pharmaceutical applications, such 
as drugs and natural health products, pH dependent controlled release 
compositions can be applied for designing compositions to be used as 
fertilizers, herbicides, diagnostic reagents, etc., as well. 
SUMMARY OF THE INVENTION 
It has now been found that by compensating part of the acetate residues in 
the starch acetate of the composition described in patent application 
PCT/FI95/00331 by dicarboxylate acid residues, a new kind of pH dependent 
controlled release composition is obtained, which is especially suitable 
for enteric use. Accordingly, the composition of the present invention 
provides a compact for enteric use, which is far easier and more 
cost-effective to prepare than conventional pharmaceutical 
entero-compositions. 
The composition is a compact consisting essentially of an active ingredient 
or active ingredients and starch acetate dicarboxylates as the main 
functional components. 
The present invention is related to a composition for pH dependent 
controlled release of active ingredients, especially drugs and natural 
health products, but also fertilizers, herbicides, insecticides and 
diagnostic reagents. The composition is a compactible mixture of the 
active ingredient and starch molecules substituted with acetate and 
dicarboxylate residues. Succinate is the most preferred example of such 
dicarboxylate residues. 
The starch molecules can have the acetate and dicarboxylate residues 
attached to the same starch molecule backbone or on separate starch 
molecule backbones. 
Methods for preparing said starch acetate dicarboxylates by 
transesterification or mixing of starch acetates and starch dicarboxylates 
respectively are described in the present invention. 
The present invention provides a compact for pH dependent controlled 
release or enteric use which is easy and cheap to prepare. By preparing 
compositions according to the present invention environmental pollution is 
diminished because the use of diluents detrimental to environment needed 
in the preparation of films surrounding conventional enteric compositions 
can be avoided.

THE DETAILED DESCRIPTION OF THE INVENTION 
In the following description, reference will be made to various 
methodologies known to those who are skilled in the art of starch 
chemistry and pharmaceutical technology. Publications and other materials 
describing the known methodologies are herewith incorporated in full. 
General principles of starch chemistry are described for example in 
Modified Starch; Properties and Uses, Ed. Wurzburg, O. B., CRC Press Inc. 
, Boca Raton, Fla., 1986 and Starch; Chemistry and Technology, Eds. 
Whistler. R. C., BeMiller, J. N. and Paschall, E. F., Academic Press, 
Inc., Orlando, 1984. 
General principles related to pharmaceutical technology are described for 
example in The Theory and Practice of Industrial Pharmacy 3rd Ed. , 
Lachman, L., Lieherman, H. A: & Kanig; J. L. (EDs), Lea & Febiger, 
Philadelphia, 1986; and Pharmaceutical Dosage Forms: Tablets volume 1, 2, 
3, Lieberman, H. A., Lachman, L. (EDs), Marcel Dekker Inc., New York, 
1980. 
General principles for pharmaceutical excipients are described for example 
in Martindale, The Extra Pharmacopeia, 30th Edition, The Pharmaceutical 
Press, London 1993 and Handbook of Pharmaceutical Excipients, 1994, 
American Pharmaceutical Association, The Pharmaceutical Society of Great 
Britain. 
Definitions 
Unless defined otherwise, all technical and scientific terms used herein 
have the same meaning as is commonly understood by one skilled in the art 
to which this invention belongs. In the description which follows a number 
of terms are extensively used. In order to provide a clear and consistent 
understanding of the specification and claims, including the scope to be 
given such terms, the following definitions are provided. 
The term "composition" is intended to mean a compactible mixture, which 
comprises two groups of compounds i.e. at least one active ingredient and 
the starch derivative according to the present invention. They are 
principally developed for oral use for humans, including pharmaceutical 
enterotablets, compactible enterogranules or enteropellets. Also natural 
health products can be used as the active ingredient. The compositions can 
also be used in veterinary medicine or they can be used to carry 
herbicides, insecticides, fertilizers, diagnostic reagents, etc. 
The term "active ingredient" is intended to mean drugs, medicines, 
vitamins, minerals, trace minerals, fibers, including glucan fibers, 
diagnostic reagents, herbicides, fertilizers, insecticides. 
The term "natural health product" is used synonymously with the terms 
"natural health food products", "health food products" and "natural 
products" and is intended to mean products obtained from nature which are 
used in a medicine-like manner as health promoting, disease preventing 
products and/or otherwise beneficial food products, which do not 
necessarily have the authorization (approval) which is required for 
registered drugs. These substances include vitamins, minerals, trace 
minerals, antioxidants, fibers, etc. 
The term "compactible" is intended to mean a mixture of the active 
ingredient and the starch derivative according to the present invention 
which, under the impact of compressing forces, forms compacts, such as 
tablets or other easily administrable dosage forms with sufficient 
breaking strength. 
The term "compact" is intended to mean compressed tablets, compacted 
granules or pellets or other easily administrable dosage forms. 
The term "starch" is intended to mean any form of starch, native or 
chemically or enzymatically hydrolyzed starch. Suitable starch is 
obtainable from barley, wheat, oats, corn, potato, tapioca, sago, rice and 
other tuber or grain based starch products, with an amylose content of 
0-100% (w/w) and an amylopectin content of 100-0% (w/w). Especially 
preferred are starch products from barley and oats, which have an amylose 
content of 20-25% (w/w). In other words the molecular weight and amylose 
content of the starch is not a restricting factor for the starch used as 
starting material in the present invention. 
The term "starch molecules substituted with acetate" is intended to mean 
that the starch molecules have been esterified with acetic acid or acetic 
anhydride or acetyl chloride and contain acetyl residues (synonymously 
used for groups or moieties), randomly distributed along the backbone of 
the starch molecule. 
The term "starch molecules substituted with dicarboxylate" is intended to 
mean that the starch molecules have been esterified with preferably 
straight or branched chain dicarboxylic acids, straight or branched chain 
dicarboxylic anhydride or straight or branched chain dicarboxylic chloride 
or hydroxy dicarboxylic acid containing the corresponding acyl residues 
with different chain lengths such including oxalate, malonate, succinate, 
glutarate, adipate, pimelate, subcrate, azealate, sebacate, maleate, 
fumarate, realate, tartrate, citrate or mixtures of these dicarboxylates. 
The most preferred dicarboxylate acid is succinate. Some tricarboxylic 
acid including citrate are incorporated in the definition of the 
dicarboxylic acid as an example of branched chain dicarboxylic acids. 
The term "starch molecules substituted with acetate and dicarboxylate 
residues" are intended to mean that they are starch molecules which are 
substituted by the residues defined above either on the same starch 
molecule backbone obtainable by e.g. transesterification methods or 
esterification with mixtures of reactive acetate or dicarboxylate groups. 
The term is also intended to mean that said substituents are present on 
different starch molecules which can be mixed in certain proportions in 
order to obtain the desired average substitution degrees. 
The term "starch acetate succinate" is intended to mean that the acetyl and 
succinyl groups are on the same starch molecule backbone. 
The term "starch molecules substituted with acetate and succinate" is 
intended to include both the starch acetate succinate and the starch 
molecule mixture which carries the acetyl and succinyl residues on 
separate starch molecule backbones. 
An "average substitution degree (DS)" is intended to mean the actual 
substitution degree of the respective residues which are randomly 
distributed on starch molecules, which are substituted randomly by both 
residues or the average DS which can be calculated from the overall 
mixture which is obtainable when starch acetate with a certain DS is mixed 
with starch dicarboxylate with a certain DS in a certain ratio. 
The term "controlled release" is intended to mean that the release of an 
active ingredient from a composition can be modified in a desired way. 
The term "pH dependent controlled release of the active ingredient" is 
intended to mean that the rate of release is dependent of or regulated by 
the pH of the surrounding media or environment. 
The term "retarded release" is intended to mean that the release is slower 
but not totally absent in acidic pH. 
The term "enhanced release" is intended to mean that the release is more 
rapid in an essentially neutral or basic pH. 
The term "essentially neutral pH" is intended to mean a pH 7 of about pH 5 
up to pH 8. pH 8 is already defined as a basic solution. 
The term "enterocomposition" is intended to mean that the controlled 
release of the active ingredient is pH dependent or pH regulated. The 
release of the active ingredient is retarded in an acidic solution and 
enhanced in an essentially neutral pH or basic pH. 
The invention relates to a composition having properties especially useful 
for enteric use. The main characteristic of the invention is that using 
starch acetate dicarboxylate, as an essential excipient in compacts, pH 
dependent active ingredient release from the compositions or dosage forms 
can be achieved. 
The composition for pH dependent controlled release of an active ingredient 
is essentially consisting of a compactible mixture of an active ingredient 
and starch molecules substituted with acetate and dicarboxylate residues. 
The dicarboxylate residues are selected from a group consisting of 
oxalate, malonate, succinate, glutarate, adipate, pimelate, suberate, 
azealate, sebacate, maleate, malate, fumarate, tartrate, citrate or 
mixtures of these dicarboxylates. The most preferred dicarboxylate acid is 
succinate. The same effect can be obtained also using a physical mixture 
of starch acetate and starch dicarboxylate instead of starch acetate 
dicarboxylate. 
The starch molecules used in the composition have an average substitution 
degree of at least 1 for the acetate residue, but the higher the 
substitution degree is, the stronger tablets are obtained. Sufficiently 
strong tablets can be obtained with starch molecules could have an average 
substitution degree of at least 1.5 for the acetate residue. However, even 
stronger tablets are obtained, if the substitution degree of at least 2 is 
used for the acetate residue. Consequently, the starch molecules used in 
the composition advantageously have an average substitution degree between 
about 1.00-2.95 for the acetate residue. 
The starch molecules used in the composition have an average substitution 
degree in the approximate range 0.05-1.5 for the dicarboxylate residue. 
Some pH dependent release can be detected with as small dicarboxylate 
substitution degrees as less than 0.05 but better results are achieved 
when an average substitution degree of 0.2-1.2 for the dicarboxylate 
residue is used. If the mechanical strength of the tablet is not a 
prerequisite property, the DS for acetate can be less than 1. By changing 
the DS of the acetate and dicarboxylate residues the functional properties 
of the tablet can be modified in desired ways. 
The composition of the present invention is typically a compact, more 
specifically for pharmaceutical application it is either a tablet, granule 
or pellet. The composition can be designed as a single unit tablet or a 
multiple unit dosage form, e.g. a gelatin capsule filled with numerous 
enterogranules or enteropellets. The composition can be modified to be 
suitable for different uses by changing the substitution degrees, molar 
mass of the starch acetate succinate polymer, by changing the shares of 
physical mixture of starch acetate and succinate, by changing the drug 
amount and amount of other excipients in the formulation. It is also 
possible to modify the pH-dependent controlled release effect or 
entero-effect by using at least two different types of starch acetate 
dicarboxylate and by using different substitution degrees in these 
dicarboxylates. It is also possible to modify the entero-effect by using 
at least two different types of starch acetate succinates with different 
substitution degrees. 
Essentially two types of starch can be used in the composition. The starch 
molecules can have the acetate and dicarboxylate residues attached to the 
same starch molecule backbone or the acetate and dicarboxylate residues 
can be on separate starch molecule backbones and combined as a physical 
mixture before compacting. 
It is however possible to replace part of the starch molecules substituted 
with dicarboxylate and succinate residues, preferably about 20-50%, most 
preferably about 30-40%, with native starch or modified starch. It is 
however essential that the composition still contains such an amount of 
dicarboxylate residues that it fulfills the DS criteria according to the 
present invention. In the composition in which the acetate and 
dicarboxylate residues are on separate starch molecules, part or almost 
all, preferably 10-99%, most preferably 20-80% of the starch acetate can 
be replaced by native starch or more preferably modified starch. The 
replacing modified starch can for example be gelatinized or cross-linked 
starches as described in Predeepkumar, P. et al., Pharmaceutical Research, 
Vol. 10. (11), 1993. 
The pharmaceutical, natural health product and diagnostic reagent 
compositions of the present invention is intended to be administered 
orally, but it is in no way excluded to use the invention to prepare 
compositions for other applications, including e.g. rectal compositions. 
The active ingredient in the formulation is not released in any essential 
degree from the composition in the acid environment of stomach, but fast 
release is achieved as soon as the composition reaches the neutral 
environment in small intestine. The entero-effect is due to the fast 
disintegration of the compact and possible also to partial dissolution of 
starch acetate dicarboxylate in neutral environment. 
Because the composition is a compact, some minor release of the active 
ingredient can occur already in stomach. This is due to the release of the 
active ingredient from the outer surface of the compact. The amount of 
active ingredient released in this phase depends on the active ingredient 
concentration in formulation as well as the compression force used. The 
amount is typically clearly less than 30%. The rest of the active 
ingredients is released rapidly in small intestine. The biphasic release 
profile, consisting of a loading dose released in stomach and a 
maintaining dose released in small intestine, is beneficial especially in 
long lasting drug therapy for reaching the relatively steady drug 
concentrations in blood. 
The composition can be prepared as essentially by four methods described 
below. These methods can be modified in several ways and there are several 
alternative methods which can be used in each step. 
Alternative 1. 
Starch acetate molecules are prepared by conventional methods. Part of the 
acetate residues in the starch acetate molecules are substituted with 
dicarboxylate residues using transesterification methods to obtain starch 
acetate dicarboxylate molecules in which the dicarboxylate residues can be 
any of those mentioned above. The most preferred being succinate residues. 
Alternative 2. 
Starch dicarboxylate molecules are prepared by conventional methods. Part 
of the dicarboxylate residues of the starch dicarboxylate molecules are 
substituted with acetate residues using transesterification methods to 
obtain starch acetate dicarboxylate molecules; 
Alternative 3. 
Starch acetate dicarboxylate molecules can be prepared by allowing a 
mixture of reactive acetyl and dicarboxyl groups to react with starch. 
These mixtures can include a mixture of acetic acid and dicarboxylic acid, 
acetyl and dicarboxyl anhydride, acetyl and dicarboxyl chloride, 
respectively. Compatible combinations of these mixtures and methods can 
also be used. 
Alternative 4. 
Starch acetate and starch dicarboxylate molecules are prepared separately 
by conventional methods. These two types of molecules are mixed together 
in desired ratios so that starch mixtures which have the desired 
properties--compactibility and pH dependent controlled release--are 
obtained. It is also possible to use instead of a single dicarboxylate 
starch, mixtures of different starch dicarboxylates. 
Finally the starch acetate dicarboxylates obtained are mixed with one or 
more active ingredient(s) and the mixture is compressed essentially as 
described in the International patent application PCT/FI95/00331 which is 
hereby fully incorporated by reference, to obtain the compacts for pH 
dependent controlled release of the active ingredient. 
Methods of preparing the starch acetate dicarboxylate molecules used in the 
present invention are described in more detail in the following examples, 
which should be read as describing the invention and not limiting the 
same. The preparation of the compacted compositions and their properties 
as well as test methods used are described in more detail in the 
experiments. The experiments should not be read to limit the scope of the 
present invention but to clarify the applicability of the invention. 
EXAMPLE 1 
The preparation of starch acetate succinate by transesterification 
Starch acetate succinates were prepared by transesterification of starch 
acetate. The quantities of reagents and reaction conditions are shown in 
Table 1. 
TABLE 1 
______________________________________ 
The preparation of starch acetate succinates by 
transesterification and reaction conditions 
Starch Succinic 
Reaction 
acetate Pyridine anhydride 
conditions 
Batch DS.sup.1 
g g g .degree.C. 
h 
______________________________________ 
No. 1 2.84 70 250 45 85-90 6 
No. 2 2.84 70 150 45 85-90 16 
No. 3 3.0 13,9 50 8,8 85-90 16 
No. 4 1.7 70 500 175 85-90 12 
______________________________________ 
.sup.1 Analysis method of the degree of substitution: Wurzburg. O.B., 
Acetylation, In Methods in Carbohydrate Chemistry, Vol. IV, ed. R. L. 
Whistler, Academic Press, New York and London, 1964, p. 288. 
Starch acetate succinates were prepared in flat flange reactor vessels made 
of glass with coil condenser, mechanical stirrer, thermometer and oil 
bath. 
Starch acetate and pyridine were mixed for 30 minutes in 90.degree. C. 
After mixing succinic anhydride was added to the reaction mixture for an 
hour. The reaction conditions used are illustrated in Table 1. After the 
reaction was completed, the mixture was cooled and precipitated from 
acidic solution with mechanical rapid stirring. After precipitation the pH 
value of the solution was 2-4. The precipitate was filtered and washed 
with water until pH value was over 5. In the end of the process the 
product was airdried. The results of the analyses of starch acetate 
succinates are illustrated in Table 2. 
TABLE 2 
______________________________________ 
Analyses of starch acetate succinates 
Degree of Dry Molecular 
substitution DS.sup.1 
content Ash weight 
Batch acetate succinate % % g/mol.sup.2 
______________________________________ 
No. 1 2.75 0.03 98.1 0.04 Mw = 117300 
Mn = 32170 
No. 2 2.38 0.03 95.4 0.27 Mw = 117300 
Mn = 32170 
No. 3 2.29 0.13 97.6 0.13 Mw = 117300 
Mn = 32170 
No. 4 1.09 0.57 98.4 0.06 Not measurable 
______________________________________ 
.sup.1 Analysis method of the degree of substitution: Wurzburg. O.B., 
Acetylation, In Methods in Carbohydrate Chemistry, Vol. IV, ed. R. L. 
Whistler, Academic Press, New York and London, 1964, p. 288. 
.sup.2 GPCanalyses were made by Alko Group Ltd. Alcohol Control Laborator 
(ACL) Equipment: HP1090, two column in series (Waters, Ultra Hydrogel 
2000), solvent 50 nM NaOH, temperature 40.degree.C., dextran standards, R 
and viscositydetectors. Only molecular weights of starting materials of 
starch acetate are measured. 
EXAMPLE 2 
The preparation of starch acetate succinate in organic solvent without 
transesterification 
The preparation of starch acetate succinate was also done without 
transesterification. The preparation was performed using both acetic 
anhydride and succinic anhydride in organic solvent. The quantities of 
reagents are illustrated in Table 3. 
TABLE 3 
______________________________________ 
The preparation of starch acetate succinates and reaction conditions 
Pyri- Acetic Succinic 
Reaction 
Starch.sup.o 
dine anhydride 
anhydride 
condition 
Batch g g g g .degree.C. 
h 
______________________________________ 
No. 5 70 250 112 43.2 85-90 3.sup.1 /6.sup.2 
No. 6 70 150 112 43.2 105 3.sup.1 /6.sup.2 
No. 7 125 250 250 125.0 85-90 3.sup.1 /6.sup.2 
No. 8 125 250 250 125.0 85-90 1.sup.3 /4.sup.2 
______________________________________ 
.sup.o Hydrolyzed barley starch 
.sup.1 Reaction time for acetylation 
.sup.2 Reaction time for the whole reaction 
.sup.3 Reaction time for succinylation 
Starch acetate succinates were prepared with the reaction equipment 
described in Example 1. 
Starch acetate and pyridine were mixed for 30 minutes in 90.degree. C. In 
Batch No. 5, 6 and 7 acetic anhydride and in Batch No. 8 succinic 
anhydride was added to the mixture and the reaction was performed using 
the reaction conditions illustrated in Table 3. In Batch No. 5, 6 and 7 
succinic anhydride and in Batch No. 8 acetic anhydride was added and 
reaction was performed using the reaction conditions illustrated in Table 
3. After the reaction was completed, the mixture was cooled and 
precipitated from acidic solution with mechanical, rapid stirring. After 
precipitation the pH value of the solution was succinates are illustrated 
in Table 4. 
TABLE 4 
______________________________________ 
Analyses of starch acetate succinates 
Degree of Dry Molecular 
substitution DS.sup.1 
content Ash weight 
Batch acetate succinate % % g/mol.sup.2 
______________________________________ 
No. 5 1.51 0.15 98.1 0.29 Mw = 117300 
Mn = 32170 
No. 6 1.34 0.25 98.7 0.37 Mw = 117300 
Mn = 32170 
No. 7 1.83 0.09 98.1 0.13 Mw = 117300 
Mn = 32170 
No. 8 0.39 1.12 95.8 0.17 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 Analysis method of the degree of substitution: Wurzburg. O.B., 
Acetylation, In Methods in Carbohydrate Chemistry, Vol. IV, ed. R. L. 
Whistler, Academic Press, New York and London, 1964, p. 288. 
.sup.2 GPCanalyses were made by Alko Group Ltd. Alcohol Control Laborator 
(ACL) Equipment: HP1090, two column in series (Waters, Ultra Hydrogel 
2000), solvent 50 nM NaOH, temperature 40.degree.C., dextran standards, R 
and viscositydetectors. Molecular weights of starch are only measured. 
EXAMPLE 3 
The preparation of starch acetate in acetic anhydride 
Starch acetate was prepared in acetic anhydride using sodium hydroxide as 
reaction catalyst. The quantities of reagents and reaction conditions are 
shown in Table 5. 
TABLE 5 
______________________________________ 
The preparation of starch acetate and reaction conditions 
Acetic Sodium Reaction 
Starch.sup.1 
anhydride 
hydroxide 
conditions 
Batch kg kg kg .degree.C. 
h 
______________________________________ 
No. 9 37.5 150 8.25 125 5 
______________________________________ 
.sup.1 Hydrolyzed barley starch 
Starch acetate was prepared in 300 dm.sup.3 reactor with mechanical stirrer 
and oil heating. Starch and acetic anhydride were mixed in 45.degree. C. 
Sodium hydroxide was added to the reaction mixture for 10 minutes. Heating 
was increased and reaction was allowed to occur using the reaction 
conditions illustrated in Table 5. After the reaction was completed, the 
mixture was cooled, precipitated from water, washed and dried. The results 
of the analysis of starch acetate is illustrated in Table 6. 
TABLE 6 
______________________________________ 
Analysis of starch acetate 
Degree of Dry Molecular 
substitution 
content Ash weight 
Batch DS.sup.1 % % g/mol.sup.2 
______________________________________ 
No. 9 2.76 83.4 0.11 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and .sup.2 compare with Table 4 
EXAMPLE 4 
The preparation of starch succinate in organic solvent 
Starch succinate was prepared in organic solvent with quantities of 
reagents and reaction conditions shown in Table 7. 
TABLE 7 
______________________________________ 
The preparation of starch succinate and reaction conditions 
Succinic Dimethyl 
Reaction 
Starch.sup.1 
anhydride Pyridine 
formamide 
conditions 
Batch g g g g .degree.C. 
h 
______________________________________ 
No. 10 
150 290 180 500 80-85 7 
______________________________________ 
.sup.1 Hydrolyzed barley starch 
Starch succinate was prepared with the reaction equipment described in 
Example 1 as described below. The results are shown in Table 8. 
TABLE 8 
______________________________________ 
Analysis of starch succinate 
Degree of Dry Molecular 
substitution 
content Ash weight 
Batch DS.sup.1 % % g/mol.sup.2 
______________________________________ 
No. 10 1.7 96.2 0.14 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and.sup.2 compare with Table 4. 
Starch and pyridine were mixed and refluxed for 90 minutes in 90.degree. C. 
Part of dimethylformamide was added to the reaction mixture and the rest 
of it was mixed with succinic anhydride and they were added together to 
the mixture. After reaction the mixture was dissolved to sodium 
bicarbonate solution and ultrafiltered. The results of the analysis of 
starch succinate is illustrated in Table 8. 
EXAMPLE 5 
The physical mixture of starch acetate and starch succinate 
The physical mixture was made from starch acetate and starch succinate. The 
preparation of these starch acetate and succinates are described in 
Batches 3 and 4, Batch No. 9 and 10. In the Table 9 the degrees of 
substitution of starch acetate and starch succinate and the average 
degrees of substitution of acetyl residues and succinyl residues in the 
physical mixture are shown. 
TABLE 9 
______________________________________ 
The degrees of substitution of starch acetate and starch succinate 
and the average degrees of substitution of acetyl residues and 
succinyl residues in the physical mixture. 
Starch Starch Physical 
acetate succinate mixture 
Acetate 
Succinate 
Batch DS DS w/w DS.sup.1 
DS.sup.1 
______________________________________ 
No. 11 2.76 1.7 1:1 1.56 0.76 
______________________________________ 
.sup.1 in mixture (average) 
EXAMPLE 6 
The preparation of starch acetate succinate in glacial acetic acid 
The preparation of starch acetate succinate was also performed using 
glacial acetic acid as intermediate agent. The quantities of reagents are 
illustrated in Table 10. 
TABLE 10 
______________________________________ 
The preparation of starch acetate succinate and reaction conditions 
Gla- Ace- 
cial tic 
acetic anhy- 
Succinic Reaction 
Starch.sup.1 
acid dride 
anhydride 
NaOH condition 
Batch g g g g g .degree.C. 
h 
______________________________________ 
No. 12 50 350 94.4 61.7 11 85-90 3.sup.2 
110-115 
3.sup.3 
No. 13 50 250 126 61.7 11 85-90 .sup. 2 
______________________________________ 
.sup.1 Hydrolyzed barley starch 
.sup.2 Reaction conditions for succinylation 
.sup.3 Reaction conditions for the acetylation 
Starch acetate succinates were prepared with the reaction equipment 
described in Example 1. 
Starch and glacial acetic acid were mixed for 30 minutes in 
45.degree.-50.degree. C. In Batch No. 12 succinic anhydride and in Batch 
No. 13 both succinic anhydride and acetic anhydride was added to mixture. 
After 15 minutes sodium hydroxide was added drop by drop and reaction was 
allowed to occur in the reaction conditions illustrated in Table 3. After 
the reaction had happened in Batch No. 12 acetic anhydride was added and 
reaction was done with reaction conditions illustrated in Table 3. 
After the reaction was completed the mixture was cooled and excess acetic 
acid was distilled in vacuum. After distillation the mixture was 
precipitated from water with mechanical rapid stirring, filtered, washed 
and dried. The results of the analyses of starch acetate succinates are 
illustrated in Table 11. 
TABLE 11 
______________________________________ 
Analyses of starch acetate succinates 
Degree of Dry Molecular 
substitution DS.sup.1 
content Ash weight 
Batch acetate succinate % % g/mol.sup.2 
______________________________________ 
No. 12 
0.18 1.36 95.6 0.06 Mw = 117300 
Mn = 32170 
No. 6 0.16 0.69 98.3 0.97 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and .sup.2 compare with Table 4. 
EXAMPLE 7 
The preparation of starch acetate succinate in glacial acetic acid by 
transesterification 
The preparation of starch acetate succinate was also performed by 
transesterification of starch acetate using glacial acetic acid as inert 
agent. Sodium hydroxide and sodium acetate were used as 
transesterification catalysts. 
The quantities of reagents are illustrated in Table 12. 
TABLE 12 
______________________________________ 
The preparation of starch acetate succinate and reaction conditions 
Starch Glacial Succinic Reaction 
acetate acetic anhydride 
Catalyst 
conditions 
Batch DS g g g g .degree.C. 
h 
______________________________________ 
No. 14 3.0 70 245 73 19.sup.1 
85-90 6 
No. 15 3.0 50 400 92.6 22.sup.2 
85-90 3 
______________________________________ 
.sup.1 Sodium hydroxide 
.sup.2 Sodium acetate 
Starch acetate succinates were prepared with the reaction equipment 
described in Example 1. 
Starch acetate and glacial acetic acid were mixed for 30 minutes in 
45.degree.-50.degree. C. and succinic anhydride was added to the mixture. 
After 15 minutes the transesterification catalyst, in Batch No. 14 sodium 
hydroxide and in Batch No. 15 sodium acetate, was added drop by drop and 
the reaction was allowed to happen in the reaction conditions illustrated 
in Table 3. When the reaction was completed, the mixture was cooled and 
excess acetic acid was distilled in vacuum. After distillation the mixture 
was precipitated from water with mechanical, rapid stirring, filtered, 
washed and dried. The results of the analyses of starch acetate succinates 
are illustrated in Table 13. 
TABLE 13 
______________________________________ 
Analyses of starch acetate succinates 
Degree of substitution 
Dry Molecular 
acetate succinate 
content 
Ash weight 
Batch DS.sup.1 
DS.sup.1 % % g/mol.sup.2 
______________________________________ 
No. 14 2.35 0.10 99.0 0.05 Mw = 117300 
Mn = 32170 
No. 15 2.90 0.10 99.2 0.17 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and .sup.2 compare with Table 4. 
EXAMPLE 8 
The preparation of starch acetate succinate in acetic anhydride 
The preparation of starch acetate succinate was also done by using acetic 
anhydride both as reagent and intermediate agent for the reaction. Sodium 
hydroxide was used as reaction catalysts. The quantities of reagents are 
illustrated in Table 14. 
Starch acetate succinates were prepared with the reaction equipment 
described in Example 1. 
Starch and acetic anhydride were mixed for 30 minutes in 
45.degree.-50.degree. C. and sodium hydroxide was added to the mixture 
drop by drop and the reaction was allowed to occur using the reaction 
conditions illustrated in Table 14. After the acetylation reaction had 
occured the succinic anhydride was added to the mixture and the reaction 
was allowed to occur in the reaction conditions illustrated in Table 14. 
TABLE 14 
______________________________________ 
The preparation of starch acetate succinates and reaction conditions 
Acetic Succinic Reaction 
Starch.sup.1 
anhydride 
anhydride 
NaOH conditions 
Batch g g g g .degree.C. 
h 
______________________________________ 
No. 16 
50 200 46.3 11 120-125 
3.sup.2 
85-90 3.sup.3 
No. 17 
50 200 61.7 11 120-125 
2.sup.2 
85-90 4.sup.3 
______________________________________ 
.sup.1 Hydrolyzed barley starch 
.sup.2 Reaction conditions for acetylation 
.sup.3 Reaction conditions for succinylation 
TABLE 15 
______________________________________ 
Analyses of starch acetate succinates 
Degree of substitution 
Dry Molecular 
acetate succinate 
content 
Ash weight 
Batch DS.sup.1 
DS.sup.1 % % g/mol.sup.2 
______________________________________ 
No. 16 2.30 0.10 98.4 0.11 Mw = 117300 
Mn = 32170 
No. 17 1.78 0.10 97.7 0.20 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and .sup.2 compare with Table 4. 
After the succinylation reaction the reaction mixture was cooled, 
precipitated from water with mechanical, rapid stirring, filtered, washed 
and dried. The results of the analyses of starch acetate succinates are 
illustrated in Table 15. 
EXAMPLE 9 
The preparation of starch acetate dicarboxylates 
The preparation of starch acetate dicarboxylates starch acetate adipate and 
starch acetate sebacate were performed by using acetic anhydride both as 
reagent and intermediate agent for the reaction. Sodium hydroxide was used 
as reaction catalysts. The quantities of reagents are illustrated in Table 
16. 
TABLE 16 
______________________________________ 
The preparation of starch acetate dicarboxylates and reaction conditions 
Acetic Dicarbocylic Reaction 
Starch.sup.1 
anhydride acid NaOH condition 
Batch g g g g .degree.C. 
h 
______________________________________ 
No. 18 
50 200 45.1.sup.4 
11 120-125 
3.sup.2 
130-135 
2.sup.3 
No. 19 
50 200 45.7.sup.5 
11 120-125 
2.sup.2 
130-135 
2.sup.3 
______________________________________ 
.sup.1 Hydrolyzed barley starch 
.sup.2 Reaction conditions for acetylation 
.sup.3 Reaction conditions for dicarboxylation 
.sup.4 Adipic acid 
.sup.5 Sebacic acid 
Starch acetate dicarboxylates were prepared with the reaction equipment 
described in Example 1. 
Starch and acetic anhydride were mixed for 30 minutes in 
45.degree.-50.degree. C. and sodium hydroxide was added to the mixture 
drop by drop and the reaction was allowed to occur using the reaction 
conditions illustrated in Table 16. After the acetylation reaction 
dicarboxylic acid was added to the mixture and the reaction was performed 
using the reaction conditions illustrated in Table 16. After the 
dicarboxylation reaction the reaction mixture was cooled, precipitated 
from water with mechanical, rapid stirring, filtered, washed and dried. 
The results of the analyses of starch acetate dicarboxylates are 
illustrated in Table 17. 
TABLE 17 
______________________________________ 
Analyses of starch acetate dicarboxylates 
Degree of substitution 
Dry Molecular 
acetate succinate 
content 
Ash weight 
Batch DS.sup.1 
DS.sup.1 % % g/mol.sup.2 
______________________________________ 
No. 18 2.0 0.1 95.8 0.14 Mw = 117300 
Mn = 32170 
No. 19 2.7 0.1 97.4 0.81 Mw = 117300 
Mn = 32170 
______________________________________ 
.sup.1 and .sup.2 compare with Table 4. 
EXPERIMENT 1 
The preparation of tablets 
Tablets, containing starch acetate succinate, anhydrous theophylline as an 
active substance and magnesium stearate as a lubricant, were compressed 
using an instrumented eccentric tablet press (Korsch, EK-0, Berlin, 
Germany) and flat-faced punches with a diameter of 1 cm. The rate of the 
tablet press was 30 rpm. Before compression all powders were stored at 33% 
relative humidity and room temperature. Pre-weighed powder samples were 
poured manually into the die cavity and compressed to form tablets using 
compression force of 15 kN. In some experiments compression force was 
adjusted to 5 kN or 25 kN. 
EXPERIMENT 2 
Dissolution testing 
The release of active substance, i.e. anhydrous theophylline, from starch 
acetate succinate tablets was determined using the USP (XXIII) rotating 
basket method at the rotation speed of 100 rpm. The volume of 300 ml of 
phosphate buffer with different pH value was used as dissolution medium. 
The concentration of phosphate buffer was 40 mM. Samples of 3 ml were 
withdrawn from the vessels at selected intervals, filtered through 0.2 
.mu.m membrane filters, suitably diluted with phosphate buffer solution. 
The experiments were accomplished for eight hours in maximum. The 
concentration of anhydrous theophylline was measured 
spectrophotometrically at a wavelength of 270 nm (Hitachi-220, Tokyo, 
Japan). 
EXPERIMENT 3 
The effect of pH of dissolution medium on drug release 
The rate of drug release from matrix tablets was determined using phosphate 
buffers of various pH values as dissolution media is shown in FIG. 1. 
Tablets consisting of 74.5% (w/w) starch acetate succinate, 25% (w/w) 
anhydrous theophylline and 0.5% (w/w) magnesium stearate were prepared 
according to the method depicted in Example 1. The degrees of substitution 
were 1.34 and 0.25 for acetyl and succinyl groups, respectively. pH values 
of buffer solutions were 1, 2, 4, 6, 7 and 8. 
The rate of drug release was delayed with decreasing pH value of 
dissolution medium. Both in basic, i.e. pH 8, and neutral, i.e. pH 7, 
medium anhydrous theophylline released completely in twenty minutes. In 
slightly acidic solution, i.e. pH 6 and 4, about 90 minutes was required 
to achieve complete drug release. Nevertheless, the rate of drug release 
was somewhat faster at pH 6 than pH 4 indicating pH dependent behaviour of 
starch acetate succinate. Drug release profiles at pH 2 and pH 1 were 
distinctly different compare to profiles obtained in basic, neutral or 
slightly acidic media. After eight hours of experiment about 99% and 83% 
of drug content of tablets was released at pH 2 and pH 1, respectively. 
The behaviour of starch acetate succinate was definitely pH dependent, 
which was an advantageous property in the field of controlled drug 
delivery. 
EXPERIMENT 4 
The effect of degrees of substitution of starch acetate succinate on drug 
release 
Drug release from tablets, containing differently substituted starch 
acetate succinate as a matrix forming substance, was examined using the 
previously described method (Experiment 2). Anhydrous theophylline content 
in each tablet was 25% (w/w). The degrees of substitution of starch 
acetate succinate polymer are shown in Table 18. Dissolution studies were 
performed in basic, i.e. pH 8, and in acidic, i.e. pH 1, phosphate buffer 
solutions. 
As the starch molecule was highly substituted with acetyl groups, i.e. DS 
was above two, the release rate of active substance was slow, particularly 
in acidic environment (FIG. 2). 
Drug release was slow also in basic solution as starch acetate succinate 
No. 1 was used to form matrix. Delayed release was probably due to the 
fairly small amount of succinyl groups, which was not sufficient enough to 
ensure rapid drug release in basic medium. In the case of starch acetate 
succinate No. 2, the succinyl content of polymer was distinctly higher 
when compared to polymer No. 1. Thus, the rate of drug release at pH 8 
accelerated (FIG. 2). 
TABLE 18 
______________________________________ 
The degrees of substitution (DS) of acetyl and succinyl 
groups of different starch acetate succinate 
Starch acetate succinate 
Acetate DS 
Succinate DS 
______________________________________ 
No. 2 (Example 1) 
2.38 0.03 
No. 3 (Example 1) 
2.29 0.37 
No. 6 (Example 2) 
1.34 0.25 
No. 8 (Example 2) 
0.39 1.12 
______________________________________ 
As the degree of substitution for acetyl groups was below 2.0 and the 
corresponding value on behalf of succinyl groups was underneath 1.0 
(polymer No. 3) release of active substance was fast in basic solution 
(FIG. 2). However, the release rate was relatively slow at pH 1. Polymers, 
with that kind of pH dependent behavior, could be beneficial in many 
applications for controlled drug delivery. 
Drug release from tablets composed of polymer No. 4, was very rapid in both 
media (FIG. 2). Acetyl contents of polymer is possibly too low to form 
proper matrix tablets. Besides low acetyl contents, the degree of 
substitution of polymer for succinyl groups was above one, which had an 
influence on the release rate of active substance, at least in basic 
solution. 
By substituting starch molecule with acetyl and succinyl groups, polymer 
with pH dependent behaviour was achieved. It is possible to affect the 
rate of drug release by varying the amounts of acetyl and succinyl groups 
attached to the starch molecule. 
EXPERIMENT 5 
The effect of compression force on the rate of drug release from the starch 
acetate succinate tablets 
Three different compression forces, i.e. 5 kN, 15 kN and 2 kN, were used to 
prepare tablets composed of 74.5% (w/w) starch acetate succinate, 25% 
(w/w) anhydrous theophylline and 0.5% (w/w) magnesium stearate. The 
degrees of substitution for the starch acetate succinate polymer were 1.34 
and 0.25 for acetyl and succinyl groups, respectively. The rate of drug 
release was examined in acidic, i.e. pH 1, and in basic, i.e. pH 8, 
phosphate buffer solution with the procedure as described previously 
(Experiment 2). 
Regardless of pH of dissolution solution, the active substance released 
relatively rapidly from the tablets compressed at the lowest force, i.e. 5 
kN (FIG. 3). The complete drug release was attained in five minutes as 
basic buffer solution was used. In acidic medium, the entire anhydrous 
theophylline content released in thirty minutes. The tablets formed at 
lower compression forces, might have fairly porous structure, which 
enables the easy and rapid penetration of dissolution solution into the 
tablet. Thus, the dispersed drug substance dissolved and were released 
faster than the dispersed drug content of very dense matrix tablet. As the 
compression force of tablets was adjusted to 15 kN or 25 kN, the rate of 
drug release was decreased remarkably in the acidic (pH 1) medium. The 
last sample was taken after eight hours and until that time approximately 
83% of anhydrous theophylline released from the tablets compressed at 
force of 15 kN. The corresponding value of tablets prepared using 
compression force of 25 kN was 78%. In basic solution the rate of release 
of active substance was rapid in spite of higher compression force. 
It was possible to control drug release from starch acetate succinate 
polymer tablet with the magnitude of compression force in tabletting. 
EXPERIMENT 6 
The effect of drug concentration on the rate of drug release 
The rate of drug release of starch acetate matrix tablets containing active 
substance, i.e. anhydrous theophylline, either 5% (w/w) or 25% (w/w) was 
examined using the previously described method (Experiment 2.). The 
experiments were performed both in acidic, is. pH 1, and in basic, pH 8, 
medium. The degrees of substitution of polymer were 1.34 for acetyl groups 
and 0.25 for succinyl groups. The compression force used to form matrix 
tablets was adjusted approximately to 15 kN. 
In the basic medium, i.e. phosphate buffer of pH 8, the rate of drug 
release was fast for both formulations (FIG. 4). About twenty minutes were 
required for the complete drug release. As the experiment was performed in 
acidic solution, tablets containing 5% (w/w) of active substance the rate 
of drug release was somewhat faster compared to the tablets with greater 
drug amount. 
The drug delivery from starch acetate succinate matrices was pH dependent 
despite the amount of active substance. 
EXPERIMENT 7 
Drug release from tablets containing equal amounts of separate starch 
acetate and starch succinate polymers 
A physical mixture containing 50% (w/w) of starch acetate (DS 2.76) and 50% 
(w/w) of starch succinate (DS 1.7) was prepared. The polymer tablet 
matrices compressed at 15 kN force were composed of 74.5% (w/w) polymer 
mixture, 25% (w/w) anhydrous theophylline and 0.5% (w/w) magnesium 
stearate. The dissolution testings were accomplished using acidic (pH 1) 
and basic (pH 8) phosphate buffer solutions. 
The release profiles of active substance, over time, from matrices 
containing starch acetate succinate polymer either in the form of chemical 
compound or physical mixture are shown in FIG. 5. The degrees of 
substitution of starch acetate succinate, having the acetyl and the 
succinyl residues attached to the same starch molecule backbone, were 2.29 
and 0.37 for the acetyl and the succinyl groups, respectively. Regardless 
of the form of polymer content in tablet, anhydrous theophylline release 
rate was more rapid in basic than in acidic environment (FIG. 5). The 
amount of succinyl residues was markedly greater in the tablets of 
physical mixture, which might be the reason for the faster release rate. 
Starch acetate succinate content in tablet enabled pH dependent release of 
active substance. By mixing separate starch acetate and separate starch 
succinate and using the prepared physical mixture to form matrix tablets, 
it was also possible to attain the same type of pH dependent controlled 
drug release. 
EXPERIMENT 8 
The effect of degrees of substitution of starch acetate succinate polymer 
on breaking strength of tablets 
A series of starch acetate succinate, with different degrees of 
substitution (Table 19.), were compressed at 15 kN force. Besides polymer, 
tablets were composed of anhydrous theophylline (25% w/w) and magnesium 
stearate (0.5% w/w). To measure the breaking strength of tablets, a 
CT-5-tester (Engineering Systems, Nottingham, England) was used. 
The acetyl residues appear to be responsible for the mechanical strength of 
starch acetate succinate tablets (FIG. 6). As the degree of substitution 
of acetyl groups was above one, the breaking strength was relatively high, 
indicating good mechanical strength, which was the most important property 
of pharmaceutical tablets. The compactibility of starch acetate succinate 
powder seemed to decline with increasing succinyl contents (FIG. 6). The 
measuring of breaking strength of tablets, compressed from starch acetate 
succinate No. 4, was not possible because tablets were too weak to handle. 
TABLE 19 
______________________________________ 
The degrees of substitution (DS) of different starch acetate succinate. 
Starch acetate succinate 
Acetate DS 
Succinate DS 
______________________________________ 
No. 1 2.38 0.03 
No. 2 1.34 0.25 
No. 3 1.09 0.57 
No. 4 0.39 1.12 
______________________________________ 
Acetyl and succinyl groups, attached to the starch molecule, and amount of 
those groups, i.e. degree of substitution, have influence on the 
compactibility of starch acetate succinate powder and thus, on the 
mechanical strength of starch acetate succinate tablets. 
EXPERIMENT 9 
The effect of compression force on breaking strength of tablets 
Three different compression forces were used to prepare tablets of starch 
acetate succinate, having the degrees of substitution 1.34 for acetyl 
groups and 0.25 for succinyl groups. The average breaking strength of five 
tablets compressed at the lowest force, i.e. 5 kN, was about 83N (FIG. 7), 
indicating reasonable compactibility of polymer. This means that the 
starch acetate succinate has the ability of powder to form dense, though 
tablets. The breaking strength of starch acetate succinate tablets 
increases with rising compression force. The breaking strength values for 
tablets compressed at 15 kN and 25 kN are about 135N and 153N, 
respectively. 
EXPERIMENT 10 
The effect of pH of disintegration medium and compression force on the 
disintegration time of starch acetate tablets 
The disintegration time of tablets, containing 74.5% (w/w) starch acetate 
succinate (degrees of substitution were 1.34 and 0.25 for acetyl groups 
and succinyl groups, respectively) was determined using the method and 
apparatus described in the European Pharmacopoeia (Ph. Eur., V. 5.1.1.). 
Tablets were compressed at three different compression force, i.e. 5 kN, 
15 kN and 25 kN. 0.1N hydrochloric acid was used as disintegration medium 
originally. After operating the apparatus for two hours the acid was 
replaced by phosphate buffer solution and a disc was added to each tube. 
pH values were 1.0 and 6.8 for hydrochloric acid and phosphate buffer, 
respectively. 
Starch acetate succinate tablets, prepared at the lowest compression force, 
i.e. 5 kN, disintegrated already in the acidic medium. The average 
disintegration time of three tablets was 552 seconds. As the compression 
forces of 15 kN and 25 kN were used, tablets did not disintegrate 
completely in acidic solution, even though disruption of tablets in some 
extent occurred. In FIG. 7 disintegration time in phosphate buffer (pH 
6.8) and breaking strength of tablets versus compression force are shown. 
In spite of the magnitude of compression force, disintegration of tablets 
was relatively rapid at pH 6.8, which is close to pH of neutral 
environment (FIG. 7). However, the average disintegration time, i.e. 361 
sec., for three tablets prepared with the higher force (25 kN) was 
obviously longer than the corresponding value, i.e. 112 sec., of tablets 
compressed at 15 kN force. 
Both compression force and pH of disintegration medium seemed to have 
influence on the disintegration of starch acetate succinate tablets. 
EXPERIMENT 11 
Microstructure of tablets of starch acetate succinate 
The upper surfaces of tablets containing starch acetate succinate with 
different degrees of substitution, theophylline and magnesium stearate 
were photographed using an electron scanning microscope (Jeol JSM 35, 
Tokyo, Japan). 
The microstructure of tablets changed clearly with varying degrees of 
substitution of starch acetate succinate (FIG. 8a-d). Dense, more matrix 
like structure could be obtained by using polymer with higher acetyl 
content, i.e. a degree of substitution above two. As the succinyl residue 
of starch acetate succinate increased and the amount of acetyl groups was 
low (FIGS. 8a-d), tablets seemed to have more porous structure and thus, 
poor mechanical strength (Experiment 9). Besides the degrees of 
substitution of starch acetate succinate, the compression force also had 
an effect on the microstructure of tablets (FIGS. 9a-c). Three different 
compression forces, i.e. 5 kN, 15 kN and 25 kN, were used to prepare 
starch acetate succinate tablets. These tablets contained polymer, which 
degrees of substitution were 1.34 and 0.25 for the acetyl and the succinyl 
groups, respectively. As well as polymer content, there were also 
anhydrous theophylline and magnesium stearate contents in each tablet. 
In FIGS. 9a-c, upper surfaces of starch acetate succinate tablets 
compressed at varying compression forces are shown. As the compression 
force increased, the structure of tablets became more matrix-like enabling 
the delayed release of active substance at convenient conditions.