AN INVESTIGATION OF THE POTENTIAL OF SOY CELLULOSE AS A TABLET DISINTEGRANT

Scanning Electron Micrographs of soy cellulose (Emcosoy) particles were studied to further the understanding of the morphology of the substance and thereby to increase the comprehension of how the excipient functions in tablet systems. Bulk swelling and water uptake were studied for Emcosoy, CLD II, corn Starch, and Ac-Di-Sol. Emcosoy had maximum swelling about 56%; followed by CLD II 49% and Ac-Di-Sol 9%. No swelling was observed in Corn Starch. An ideal disintegrant should perform uniformly in pH range of gastrointestinal tract in order to disintegrate the tablet. When Emcosoy and Ac-Di-Sol were tested against various pH values, there was no significant difference in swelling of these disintegrants. Since alcohol and sodium lauryl sulfate are often used as dissolution media, the effect of different concentrations were also observed on Emcosoy and Ac-Di-Sol. There was no significant effect. Another important preformulation test reported in this thesis is a comparative study of the viscosity of different concentrations of various disintegrants. When a tablet disintegrant reacts with water a gel may be formed. If the gel is too viscous, it impedes the water penetration in the tablet. Generally it can be said that the cellulose group of disintegrants (Ac-Di-Sol, CLD II and Emcosoy) had a viscous gel compared to starch group of disintegrants (Corn Starch, Explotab and Sta-Rx 1500). If the viscosity of the gel of starch group of disintegrants has to be arranged indescending order then Explotab is followed by Sta-Rx 1500 which is followed by corn starch. If the viscosity of the gel of

Another important preformulation test reported in this thesis is a comparative study of the viscosity of different concentrations of various disintegrants. When a tablet disintegrant reacts with water a gel may be formed. If the gel is too viscous, it impedes the water penetration in the tablet. Generally it can be said that the cellulose group of disintegrants (Ac-Di-Sol, CLD II and Emcosoy) had a viscous gel compared to starch group of disintegrants (Corn Starch, Explotab and Sta-Rx 1500). If the viscosity of the gel of starch group of disintegrants has to be arranged indescending order then Explotab is followed by Sta-Rx 1500 which is followed by corn starch. If the viscosity of the gel of ii cellulose group of disintegrants had to be arranged in descending order then CLD II is followed by Emcosoy which is followed by Ac-Di-Sol.
Plastic deformation and elasticity of various disintegrants were studied using a Universal Instron Testing Machine. High plastic deformation of the disintegrant particles, may be advantageous since the deformed particles are " " energy-rich and that energy is released when the particles are exposed to water. The energy-rich particles probably swell more rapidly in water, unlike undeformed grains, which require more energy of swelling in order to well. Ac-Di-Sol particles have good plastic deformation compared to Emcosoy and Explotab particles. The three major mechanisms of ( disintegrant action are : (i) swelling (ii) capillary action (wicking) and (iii) deformation. Emcosoy particles swell considerably and they have good wicking effect, but they have poor plastic deformation.
Following the performulation study, Emcosoy (soy cellulose) was compared with other disintegrants in about 45 formulations.
About 100 dissolution profiles were obtained on various vitamin formulations using either Emcompress or Endex as the tablet matrix.
Emcosoy is as effective a disintegrant as Ac-Di-Sol and very much more effective than Corn Starch. Grateful acknowledgment is made of the invaluable cooperation and support of Edward Mendell Company,and special thanks to Dr. Joseph L.
Kanig for his advice during the study.
Appreciation is also acknowledged of the invaluable cooperation of Dr. Joan M. Lausier in solving many problems with the tablet press. Grateful acknowledgment is also made of the invaluable cooperation of Dr. Chong M. Lee

I. INTRODUCTION
There are two classes of drugs administered orally in tablet dosage form. These are: (1) insoluble drugs intended to exert a local effect in the gastrointestinal tract (such as many antacids and absorbents), and (2) soluble drugs intended to exert a systemic drug effect following their dissolution in the gut and subsequent absorption.
In the case of drug products intended to exert a s ystemic effect, the design of a dosage form which rapidl y disintegrates and dissolves may or may not be critical, depending on whether the drug is absorbed in the upper gastrointestinal tract or more generally throughout the intestinal tract. Because dosage forms must be designed to disintegrate or dissolve to release the drug in an available form at or above t h e region of absorption in the gut, the design must also be based on the solubility properties of the drug at or above its absorption site.
The present study covers the bioavailability consideration of the tablet as a dosage form, the disintegration process in general, and the information about a few widely accepted new disintegrants. The mechanism of disintegrant action will be discussed with the help of numerous references on the subject. Unfortunately, Proctor's concern was not shared by other scientists.
The need to quantify tablet disintegration by official standards was not recognized until just prior to World War II, and specifications for tablet disintegration did not appear in the USP until the fourteenth revision which was published in 1950. During the course of subsequent disintegration testing experiments, it was theorized and eventually proven that drug dissolution must follow tablet disintegration if bioavailability is to occur (6).
The topic of bioavailability has now become of interest to government; the FDA (Food and Drug Administration) has already issued specifie regulations on bioavailability.
When a drug in a dosage form is administered to a patient, the first steps in the sequence whereby the drug reaches the site of action are commonly disintegration and dissolution. The importance of these processes is year or dollar value of drug dispensed (7). The process of disintegration, dissolution, and absorption can be outlined as follows (8): Tablet or Capsule Disintegration) (1) Granules or Aggregates Deaggregation) (2) Dissolution (3) Drug in Solution (in vitro or in vivo)

Drug in Blood, Other
Fluids and Tissues Absorption (in vivo) Fine Particles (3) Before drugs can effectively pass through the gastrointestinal wall, they must be in solution. Drugs which are only sparingly soluble in the gastrointestinal content at or above their absorption site can have, as the controlling process affecting their absorption , the rate of drug solution in these fluids. In this type of s y stem, the drug goes into solution at a slow rate, absorption occurs almost immediately and is ( s not, therefore, the rate-limiting step. In one study, Nelson (9) correlated the blood level concentration of various theophylline salts with their dissolution rates.
Drugswhich exert a systemic effect must dissolve as a prerequisite to effective drug absorption. The various processes of tablet making, including the aggregation of drug into granular particles, the use of binders, and the compaction of the system into a dense tablet, are all factors which militate against a rapid drug dissolution and absorption in the gastrointestinal tract. In considering, in a general manne~ the availability of drugs from various classes of dosage forms, drugs administered in solution will usually produce the most available drug product, provided that the drug does not precipj_tate in the stcraach or is not deactivated there. The second most available form of a therapeutic agent would be drug dispersed in a fine suspension, followed by micronized drug in capsule form, followed by uncoated tablets, with coated tablets being the least bioavailable drug product in general. In formulating and designing drug products, as well as in considering methods of manufacture, the fact that the tablet dosage form is one of the least bioavailable forms (all other factors being equal) should be kept in mind (10).
Many factors can affect drug dissolution rates from tablets; hence, possibly drug bioavailability , including the crystal size of the drug, tablet disintegration mechanisms and rates, the method of granulation, ( 6 type and amount of granulating agent employed, type, amount and method of incorporation of disintegrants and lubricants, and other formulations and processing factors. Levy,et al (11), showed the effect of granule size upon the dissolution rate of salicylic acid. Salicylic acid of two mesh ranges containing 300 mg of aspirin and 60 mg of starch, were compressed at 715 kg cm-2 . The 60 to 80 mesh granules had better vitro bioavailability than 40 to 60 mesh granules.
Lachman, ~al (12), studied the effect of crystal size and granule size on a delayed-action matrix using tripelennamine hydrochloride. He notes that while granule and crystal size both affected release rate, in this instance the crystal size played a greater role than granule size in dissolution rate.
Paul, et al (13) showed that with nitrofurantoin there was an optimal average crystal size of about 150 mesh, which resulted in adequate drug excretion (hence, absorption and efficacy), but minimized emesis. This exemplifies a situation in which too rapid drug dissolution in the stomach may produce nausea and emesis; an intermediate release rate reduced this effect while achieving adequate bioavailability.
Numerous accounts of the effect of particle size on dissolution rate of steroids have been reported. In one study, Campagna,~al (14),showed that, in spite of good disintegration, therapeutic inefficacy of prednisone tablets could occur.
( 7 As discussed above, bioavailability of the drug depends on many factors.
The ensuing discussion will focus on the disintegration process, disintegrants available, and the mechanism action of disintegrants.

Disintegration of a Tablet and Disintegrants
Complete tablet disintegr?tion is defined by NF XIII (15) as: II that state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen is a soft mass having no palpably firm core." This often makes tablet disintegration a necessary first step to achieve rapid availability of the active ingredient(s). The importance of tablet disintegration was recognized as early as 1879, when a patent recommended that pills be perforated to admit gastric juice for better disintegration (16).

Reasons for Measuring Disintegration Times and Rates of Dissolution
(i) For research purposes to elucidate the mechanism involved in the processes and to determine the relative importance of the various variablesinvolved in the process of disintegration, deaggregation, and dissolution.
(ii) For developmental purposes to guide the pharmaceutical formulator in the preparation of optimum dosage forms of drugs for clinical trial.

8
(iii) For control purposes to ensure that a given pharmaceutical ( product is essentially uniform from lot to lot. (iv) For predictive purposes so that one may estimate rate(s) of absorption in man from measurement of disintegration time and/or rates of dissolution in vitro. Such predieting requires careful correlation of in vitro and in vivo results.
Our discussion of disintegration will be confined to uncoated tablets designed to release all the active ingredient(s) rapidly.
The disintegration of a tablet depends on compression force, tablet hardness,propertiesof fillers and active ingredients, properties of binders,propertiesand concentration of disintegrant and the properties of lubricants. All these factors play an important role in tablet disintegration. If we keep other factors identical (compressive force, fillers, active ingredient binders, and lubricant) in two formulations but select two different disintegrants at the same concentration for these two formulations, the in vitro bioavailability will entirely depend on the quality of the disintegrants. The drug will be released quickly from a tablet which disintegrates faster because it has better disintegrants. Thus, the disintegrants play a role in the disintegration process. The ensuing discussion will focus on different disintegrants.
( 9 Disintegrant is a term applied to substance added to a tablet granulation for the purpose of causing the compressed tablet to break apart when placed into an aqueous environment. The disintegrant in a tablet formula may be considered as a dispersing agent for the dry compacted tablet mass in the gastric milieu. Ideally, it should cause the tablet to disrupt not only into the granulated form which it was compressed, but also into the powder particles from which the granulation was prepared. The function of the disintegrant is, in effect, to counteract the action of the tablet bindersand the physical forces of compression necessary to form the tablet. The stronger the effect of the binder, the more efficient must be the disrupting effect of the disintegrant in order to release the active ingredient in the gastrointestinal tract (17).
There are two methods used for incorporating disintegrating agents into tablets. These methods are called external addition and internal addition. The most common method is the external addition method in which the disintegrant is added to the sized granulation with mixing just prior to compression. In the internal addition method, the disintegrant is mixed with other powders before wetting the powder mixture with the granulating solution. Thus, the disintegrant is incorporated within the granule. When this method is used, part of the disintegrant is added internally and part by external addition. Many experts believe that use of the two-step method usually produces better and more complete disintegration than the usual method of adding the dis-( ( 10 integrant to the granulation surface only.
Six basic categories of disintegrants have been described: starches, clays, celluloses, algins, gums, and miscellaneous. Many disintegrants have also been shown to possess binder or adhesive properties.
Since disintegration is the opposite operation to granulation (agglomeration) and the subsequent formation of strong compacts, one must carefully weigh these two phenomena when designing a tablet (18).
Formulators have tried a number of materials as tablet disintegrants with varying degrees of success. Lowenthal tabulated all the disintegrants with their pertinent references in a review article of "Disintegration of Tablet," in Journal £f Pharmaceutical Sciences (19).
In the past six to seven years, exciting developments have occurred in the area of tablet disintegrants. A nurr,ber of new disintegrants have been marketed in this period. Attention will be focused on these ''super disintegrants~ as they are called, because of their remarkable quality as disintegrants.
(i) Direct-Compression Starch: One of the most significant modifications of starch for (iv) Cross-Linked Polyvinylpyrolidone: Cross-linked polyvinylpyrolidone (PVP) is a homopolymer of N-vinyl-d-pyrolidene and has been marketed as Polyplasdone-XL (GAF Corp., New York, New York). Because of its high molecular weight and cross-linked structure, it is insoluble in water but is still very hydrophilic. The particles of PVP are porous in nature. As water is absorbed into the porous structure of the agglomerates, the lattice structure of polymer expands, causing high stress on surrounding tablet components.
The porous nature of the particles provides intraparticulate wicking of water. Like cross-linked carboxymethyl cellulose, cross-linked PVP has the ability to shrink to its original particle size when dried and then expand again when rewetted.
Both cross-linked carboxymethyl cellulose and cross-linked PVP would thus appear to be effective disintegrants in tablets made by wet granulation, as well as in those produced by direct  (21); potato, corn and wheat (22); and potato, wheat, and rice (23).
Tablets made with low pressure have high porosity, and hence, too much space. When starch swells, no pressure is exerted; therefore, disintegration is slow. Medium pressure allows just enough space so that when the starch swells, it exerts pressure on the granules to cause disintegration. High pressure, producing low porosity, decreases the ability of fluid to enter; so, disintegration is again slow (24,25).
Starch swelling was claimed to be dependent upon amylase and ( 14 arnylopectin content; the amylopectin expands, and the amylase gives osmotic pressure (26) .
Borzenou and Nesmiyan (27)  Many substances swell to a greater degree than the starches, but are poorer disintegrants. Amylase does not swell but has been stated to cause good disintegration (29). Although starch grains swell in water according to some views which I do not share, the rate and extent of swelling is still debated (30)(31)(32).
Whenever swelling of disintegrant particles take place with great force, it overcomes the adhesiveness of other ingredients in a tablet and causes the tablet to fall to powder.
The rate of penetration of fluids into a tablet is proportional to mean pore diameter or porosity (51-52); corn and starches increase penetration of fluids into tablets. Permeability of tablet decreases as pressure increases. The effect of starch on porosity may be due to its poor ability to bond and compress (52). In 1955, Curlin reported that although aspirin tablets containing starch disintegrated in 15 seconds, starch grains I \ were not swollen; nevertheless, a drop of dye solution placed on the tablet penetrated rapidly. He suggested that the disintegrating action of starch was due to capillary action, rather than to swelling (53).
Wicking is due to capillarity of fibers. Stiff fibers of uniform structure and resistance to collapse are required for good wicking. The fibers should have zero contact angle and should not swell (54). This would appear to rule out any wicking effect due to starch or cellulose fibers.
( 16 The existence of pores or capillaries is not the complete answer to the mechanism of action of disintegrants, because semipolar and nonpolar fluids penetr~te into tablets (55), yet do not cause the tablets to break. Also, tablets do disintegrate with minimum porosity (56).
(iii) Deformation: Plastic deformation of starch grains under high pressure has been reported by a number of investigators (57). Starch grains are generally thought to be elastic; therefore, any grains that are deformed under pressure tend to return to their original shape and size when the pressure is removed. However, it has been suggested that compression may cause more permanent deformation that the deformed starch grains are energy rich and that this energy is released when the grains are exposed to water (58). The energy-rich starch grains swell rapidly in water, unlike undeformed grains, which require more heat in order to swell.
The various mechanism of disintegration action discussed under a separate heading, interrelationships, probably occur in almost all tablet formulations.

Objective and Justification for the Present Study:
As discussed earlier, tablet disintegration has been increasingly viewed as an important factor in formulating pharmaceutical systems.
Mechanisms by which tablet disintegrants function have been investigated.
The current concern about bioavailability of drug products has made formulators very selective in the use of disintegrants. The United States Pharmacopoeia is presently considering a radical extension of dissolution test requirements to most conventional tablets and capsules, and thus a number of formulators are now re-evaluating their formulations to see whether it is now appropriate to alter the identity or quantity of disintegrant (59) .
The pharmaceutical industry has been using corn starch and guar gum extensively as tablet disintegrants for many years. Both dis-I integrants are natural source materials, but their function as a tablet disintegrant are not satisfactory. There is, however, a demand from certain segments of the pharmaceutical industry, particularly those concerned with vitamin formulations, which require a powerful disintegrant of natural origin.
Soy cellulose (Emcosoy), is an all-natural source material, derived from defatted soy beans by a special process. It contains no sugar or starch, and it has been given GRAS status (Generally Regarded M any formulators are not aware of the potential of this material because of the lack of authentic and extensive study . It is hoped that the present study will provide a reliable evaluation of soy cellulose (Emcosoy) as an effective substitute for corn starch and guar gum.  There are several tests which can be used to evaluate disintegrants before using them in actual formulations. No one test is perfect; each has its advantages and disadvantages. The behavior of disintegrants alone could be vastly different compared to their behavior in compressed tablets. Some of these tests may, however, be useful as the basis of a raw material specification designed to control lot-to-lot variation.
1. Scanning Electron Micrographs: The role of particle morphology(size, shape and composition) in the production of tablets has long been discussed. This theoretical effort has found an a ·lly in scanning electron microscopy (SEM), which has made it possible to obtain direct photographs of tableting excipients and finished compacts. This instrument provides scanning electron micrographs of a range of disintegrating agents, lubricants, and glidants in an attempt to further the understanding of the morphology of those substances and thereby to increase the comprehension of how the excipients function in tablet systems.
An adhesive was placed on a metal stub, which was coated with gold or cadmium.
b. A few disintegrant particles were sprinkled on the stub.

Bulk Swelling and Water Uptake:
One relatively simple test used by many groups involved in the evaluation of tablet disintegrants is the quantification of the interaction of a bulk powder bed, composed of pure disintegrant, with water. There are several types of apparatus which can be used for this purpose. The one used in this study consistedof a calibrated glass reservoir (containing water or other approp~iate fluid), .connected at its base by a U-tube to a second glass reservoir which contained the disintegrant powder  (1) where s 0 is the disintegrant level in the tube at time zero, and St is the disintegrant level in the tube at any time t.
where v 0 is the water level in the calibrated reservoir at time zero, and Vt is the water level in the calibrated reservoir at time t.
Percentage of swelling and water uptake were plotted versus time. This test is helpful in determining the ease and extent of ' bulk powder interaction with water ( 61 ).
The disintegrants used for this test were Emcosoy, Ac-Di-Sol, corn starch, and CLD II. The solvents were distilled water, ethanol/water mixtures, and sodium lauryl sulfate solutions.
Air pressure was used to remove air bubbles from the lower funnel shape portion of the reservoir. The apparatus was left undisturbed for half an hour, so the water levels in both reservoirs remained constant. The readings were taken initially at short intervals, but later at an interval of twenty minutes. Although the mechanism of disintegration is very complicated and has not been completely determined (40), the penetration of liquid into a tablet is the first step in the process of tablet disintegration.
In this test the water penetration in various disintegrants was compared.
p Where 6H is the heat wetting. If systems are not disturbed during the wetting process, 6H is independent of temperature. In this experiment, pressure p is considered constant; solving above equation.
y Cose = 6H CT (8) is obtained, where C is the positive constant; combining all abovementioned equations: k y e-/RT

2A
Since generally 6H/CT is coming between one and two, taking logarithm of equation, approximating log (6H/CT -1) to 6H/CT + C" We can obtain value of k from slope of each straight line and then Emcosoy was wetted with excess of water in a petri dish (diameter 22 cm). Then the first batch was dried at room temperature (21 C) , ; second and third batches were dried inside the oven at 40C and and 60C respectively. The cake-like mass that formed on drying was reduced to fine particles by using a Fitzpatrick Comminuting Machine. The sieve, #00, was placed at collecting end of machine.
The particles received through the "OO" sieve passed through the 100 mesh (U.S. Standard) screen.
The bulk swelling was determined by using the D-tube-type apparatus for all the batches. The batch which was deemed most promising in all respects was -compressed as formulation IV.
Tablets from· both batches were made at identical press settings,using original Emcosoy for comparison purposes. Tab (13) o is the portion of the solution which is subjected to stress. % is the torque reading.
Spindle: Big to small (1 to 7) Twenty, fifty, and a hundred rpm were used. The dial reading was taken when the pointer had completed one full return.
The easiest method of calculating viscosity is to use the Brook-  ( 63). These grains returned to their original shape when the tablets were exposed to moisture.
We can classify various disintegrant particles into two categories: those permanently deformed by the compression (in other words, these particles are nonelastic particles); and those much less permanently deformed by the compression (elastic particles).
In the past, the scanning electron microscope was used for gaining  The chart paper had ten big divisions, and each big division was divided into ten small divisions; so the total number of small divisions was one hundred. A mobile recorder pen moved along the base line of the paper, with the movement of piston. Whenthe piston applied pressure on the disintegrant particles, the pen moved on the calibrated chart paper; so by counting the small divisions, one can determine the pressure applied by the piston.
The piston can move down and up once or more times; that· makes it possible to apply single compression or cyclic compression.
The data was interpreted as follows: e. Disintegration: Tablet disintegration was tested by using the U.S.P. apparatus wit~ discs as described in the National Formulary XIV (68). f. Dissolution: Drug dissolution was measured using a U.S.P.
apparatus, and according to monographs in U.S.P. XX.
Plots of these readings were made to depict the dissolution process.  The computer program appears in Appendix  (20). This mechanisn of tablet disintegration is so effective that Emcosoy can be used as a tablet disintegrant in concentrations as low as .5%. All the disintegrants had equal initial volume in the calibrated tube, since the volume difference was used in calculating percentage swelling.

Bulk Swelling and Water
For one disintegrant,different initial weight would give different percentages of swelling as found out in Ac-Di-Sol, Table IV, and graph on page 54. Logarithm of percentage swelling vs. time would give almost a straight line (Fig. 7 ). For different initial weight, the amount of water that would travel in a powder bed would vary (Fig. 8 ) .
The amount of water travel would reduce as the weight of the disintegrant increased.
The percentage of swelling decreased with increased initial weight of the disintegrant because the particles in the bottom portion of the tube came in contact with water of the reservoir first; they tried to swell, but their swelling was reduced by the weight of particles on the top. As the weight of the disintegrant was increasing, the bulk of particles on top was increasing; at the same time the amount of particles which were in contact with water remained the same. So, the swelling was reduced with increases in weight of the disintegrant.
Average bulk swelling of Emcosoy, Ac-Di-Sol, CLD, and corn starch were compared. Time required to reach the swelling and amount of water travelled in various disintegrantswere compared (                 reduced the swelling of Emcosoy significantly.

It was observed that very dilute alcohol solutions and Sodium
Lauryl Sulfate solution reduced the surface tension of water, and they also acted as a wetting agent and enhanced the absorption of water by Ac-Di-Sol; but as their concentration increased, they ceased to act as wetting agents and there was relatively small proportions of water available for disintegrant to absorb. Therefore, swelling was reduced or, in some cases, swelling did not occur.

Sn
Where L is the penetrating length at time t, r is the average radius of void space, 8 the contact angle between liquid and powder surface, g the acceleration constant of gravity, and y, n, and d are the surface tension, viscosity, and specific gravity of liquids, respectively. The penetration rate also depends on the viscosity of gel formed by the interaction of water and disingegrant. If the gel formed is too viscous, it would impede the further penetration of water in a disintegrant bed. All these factors will be discussed in great detail separately.
In addition to water, water-alcohol mixtures of different strength, The value of energy of wetting obtained by this method according to some critics is an apparent value, since they believe that the approach is too simplified to give any real values.

Wetting and Drying of Disintegrant:
Emcosoy batches were prepared under different conditions. Bulk swelling was determined for these batches. Results are tabulated in Table XX.
As it can be seen from the Emcosoy table that was dried at room temperature and at 40chad a bulk swelling less than the untreated (original) ·Emcosoy. One reason could be that these samples were dried at low temperatures, and therefore significant amountsof surface moisture was left in these samples; that could have resulted in low water uptake and less swelling.   When the cake is baked, the surface area of the cake increases enormously, and the same thing can happen in the disintegrant particles.
The increase in surface area could lead to increased water uptake and increased swelling. Emcosoy dried at 60c had an improved flow and high density compared to the original Emcosoy. The color change was from yellowish white to brown. No swelling was observed in the first two minutes in the original Emcosoy, but there was 30% to 35% swelling in the first two minutes in Emcosoy dried at 60 c. Wicking effect was very much improved in the Emcosoy dried at 60 c --the time that was taken by the water to travel through the entire powder bed was 60 minutes, compared to 90 minutes for the original Emcosoy.
There was little offending odor from Emcosoy dried at 40 c and 60 c, and visible mold growth in Emcosoy which was dried at room temperature.
Published literature on the subject indicates that molds require a water activity number of 0.75, and bacteria requires 0.88. Below these values, microbial growth cannot be supported. It has been estimated that Emcosoy with a 10% moisture content = water activity number 0.5; and with 20% moisture content, there exists a water activity of 0.88. Since original Emcosoy usually contains less than 10% moisture, it theoretically cannot promote microbial growth. However, in a ( wet granulation process, this argument might not betrue all the time. Prolonged storage or improper storage may lead to higher moisture content and consequently makes this disintegrant vulnerable to microbial growth. c As discussed above, that Emcosoy dried at 60 had a better physical property than the original Emcosoy; they both were compared in actual tablet formulation. Original Emcosoy was identified as "A:' and the processed Emcosoy was identified as "B." In order to get unbiased evaluations of these disintegrants, the tablets were prepared and tested by my colleague. The results and other details are shown in a tabular form (Table XXI) .
As it can be seen from the table and contrary to expectation, processed disintegrant tabletshad higher disintegrant time; in other words, the tablets made using it took a long time to disintegrate, compared to tablets made using original Emcosoy. The reason could be poor deformation of processed disintegrant. The three major mechanisms of disintegration are: (1) swelling, (2) porosity and capillary action (wicking), and (3) deformation. As mentioned above, processed disintegrant is better than original Emcosoy in the first two categories.
There is no data to compare the third one. When the tablet is compressed, the compression may cause more permanent deformation in original Emcosoy than the processed Emcosoy. When the tablet is put into a disintegrating medium, the energy-rich Emcosoy grains swell rapidly, unlike processed Emcosoy grains, which require more heat in order to swell. The overall effect leads to an early disintegration of the    ( 6 ). They compared two percent aqueous dispersions of various starches, cellulose products, and of cross-linked PVP in water-diluted hydrochloric acid, (1:100) were shaken periodically, and were allowed to stand overnight.
They found that all the disintegrantshad different swelling; in some of the disintegrants, the swelling was enhanced or supressed in acidic medium.
It is expected of ideal disintegrants that its swelling should remain unchanged or preferably increased in acidic medium, since most of the tablet disintegrates in acidic environments of the stomach.  In practice, Explotab is much more superior to corn starch; the reason is that in addition to viscosity, there are other important factors, such as rate and extent of swelling, wicking effect, and deformation play crucial roles in disintegration mechanism.
Explotab, Emcosoy, Ac-Di-Sol, and corn starch were compared in actual tablet formulations. The viscosity of the gel of Explotab is greater than that of Emcosoy. The viscosity of Emcosoy is greater than that of Ac-Di-Sol. Vitamin formulations studied clearly indicated that Explotab is inferior to Ac-Di-Sol and Emcosoy. Viscosity study provides the answer. Explotab swells much more compared to Ac-Di-Sol and Emcosoy, and we therefore expect it to be better disintegrant compared to Ac-Di-Sol and Emcosoy. However, that is not true, because Explotab forms very viscous gel, and it will be shown later that it has poor deformation.
The disintegrant solutions were subjected to different shear rate, and the viscosity were determined. The rheological profiles of the various disintegrants were shown in Fig, 15 to 18 . In theory, there were all three kinds of profiles, as shown in Figure 14. In Newtonian liquids the viscosity remains unchanged with the increase in shear rate.   High hydration capacity indicates that the disintegrant requires less amounts of water to wet itself thoroughly. It can be theorized that a disintegrant with high hydration capacity would relatively have smaller water uptake in order to achieve disintegration of the tablet, compared to a disintegrant with low hydration capacity. It can be said from the data that as the viscosity of the gel of disintegrant increases, the maximum hydration capacity decreases.

Sieve Analy sis:
Nogami, et al, found that there should be the critical amount of starch necessary for the ~isintegration depending upon the particle size or specific area of ingredients. The smaller the particle size of aspirin, the more amount of starch was required for the tablet disinte-  gration. The tablet of the smallest aspirin (11.9 in mean particle size) did not disintegrate by the addition of 20% of starch. Thus, the particle size of the ingredients play an important part in tablet disintegration (71).
Rudnic, et al, studied the different particle size grades of crosslinked polyvinylpolypyrrolidone (Polyplasdone,G.A.F. Corporation) in direct compression tablet for~_ulati o ns showed tMt i1'l.<!!i'\'~a.ses in mean particle size enhanced powder flow, disintegration and dissolution, although hardness and friability were slightly better for tablets made from the finer grades ( 72). Therefore, particle size of the ingredients, as well as disintegrants, are equally imp ortant.
There is nothing like optimum particle size of disintegrant or matrix. Particle size varies for various disintegrants and tablet matrices . However, the par ticle size should be such that disintegrant can be mixed and distributed uniformly with the rest of the ingredients.
The particle size of Emcosoy was determined using sieving. Table XXV shows the size-weight distribution of Emcosoy as measured by U.S. Standard sieves.

Plastic Deformation and Elasticity of Various Disintegrants:
Modulus of elasticity at various attempted deformations and compressive force needed to achieve that deformation were tabulated in Table X1.1!I.The percentage of plastic deformation and the percentage re-   From the elasticity data, the disintegrants were arranged in the decending order of their elasticity on page 96. The order remained unchanged for CLD II, polyplasdone-XL, and Emcosoy at 10%, 20%, and 40% attempted deformation.
Force required to achieve various percentage of deformations for various disintegrants was tabulated on page 98. The force needed to attain 20% deformation in CLD II was little more than double of the force needed to attain 10% deformation in the same disintegrant.
Similar observation was made in polyplasdone-XL, and to some extent in Emcosoy. However, when the deformation was doubled from 20% to 40%, the force needed to achieve that deformation was almost five to six times than the force needed to achieve 20% of deformation. From these results, it was concluded that it was easy to deform particles initially; but as the percentages of deformation increased, the task became very difficult and greater force was needed to achieve those deformations. It was also observed that unusually high force was needed to achieve even 10% deformation in Explotab. It might be due to high degree of cross-linking among starch glycolate molecules. Cross-linked polymers of starch are more elastic, compared to their cellulose counterparts. At 20%, attempted deformation starch polymers required much more compressive force compared to cellulose polymers.
( 95 The percentages of plastic deformation and the percentages of recovery at various attempted deformations for different disintegrants were tabulated on page 93. As it could be seen from the table, at 10% attempted deformation Ac-Di-Sol had more plastic deformation than Sta-Rx 1500 and CLD II, but at 20% attempted deformation order was reversed. It was clear from the data that the initial deformation might be more in Ac-Di-Sol compared to Sta-Rx 1500 and CLD II, but the additional deformation --the deformation after some initial range --was less compared to Sta-Rx 1500 and CLD II, which indicated that Ac-Di-Sol particles deformed initially easily but later they resisted more deformations.
The recovery was least at 10% in Ac-Di-Sol, but at 20% the recovery was more than those of Emcosoy, CLD II , and Sta-Rx 1500.
The disintegrants were arranged in decending order according to the plastic deformation (at 10% atteIT>ted deformation) on page 97 .
The deformed particles are energy rich, and that energy is released when the grains are exposed to water. The energy-rich particles swell more rapidly in water, unlike undeformed grains, which require more heat in order to swell. These data provide an answer that why Ac-Di-Sol containing formulations had better disintegration and dissolution  Tables XXVIII through XXXII show physical properties of the tablet   formulae I, II, and III. High weight variation, thickness and high hardness variation were observed in multivitamin formulation (Formula I). Capping was observed in a formulation having Emcompress as a matrix. Emdex matrix formulation ~ave friability less than .90%. Disintegration time was less than 20 minutes in most of the formulation                                 Fcrn.i.larior:: Fyridc-15ne' P.c 1 37.
Dissolution profile of pyridoxine formulation containing 0. 5           Dissolution profile for Pyridoxine formulation containing 3% of Corn starch.
Emdex as a matrix.
Dis5clution Frofi1e~.    Emcosoy was tested for three major mechanisms of disintegration: (i) swelling, (ii) porosity and capillary action (wicking), and (iii) deformation. Swelling and wicking were adequate in the comparison of other satisfactory disintegrants, but Emcosoy had a poor plastic deformation. The viscosity of the gel produced by Emcosoy on wetting is less than the gel produced by CLD II, but higher than that by Ac-Di-Sol. All these factors were considered separately; but in actual disintegration of a tablet, inter-relationships always take place.
Proper storage precautions are advised for this disintegrant because it has a tendency to promote microbial growth in the presence of high moisture at room temperature as observed during the wetting and drying test.
In this project, a total of 45 tablet formulations were studied, and about 100 dissolution profiles were obtained on various vitamin formulations using either Emcompress or Emdex as the tablet matrix.
The results obtained clearly indicate that: 1. Emcosoy is superior to corn starch as a tablet disintegrant at two or three percent levels; 2. Emcosoy competes favorably with other disintegrants, such as Explotab and Ac-Di-Sol, at half, one, and two percent levels  The author would have liked to change the particle size of Emcosoy to determine its effect on disintegration and other properties of the tablet.
Emcosoy has one great advantage over other popular disintegrants in that it is of natural origin. If we want to retain this advantage, there is very little we can do to change its property. It would be of great advantage to reduce the proteinaceous fraction of Emcosoy composition (at present, about 17.5%) by some changes in processing procedure. The author anticipates that such changes would improve the plastic deformation of the Emcosoy particles; and consequently, the disintegration property. Low protein fraction would also help in protecting disintegrant at higher moisture level from lumping, as well as from microbial degradation.    . , 15 20 Concentration /lg/ml.