United States Patent (19) 11) 4,369,308 Trubiano (45) Jan
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United States Patent (19) 11) 4,369,308 Trubiano (45) Jan. 18, 1983 (54) LOW SWELLING STARCHES AS TABLET 4,219,646 8/1980 Rubens ................................ 536/109 DISINTEGRANTS 4,228, 199 0/1980 Chiu et al. ........................... 426/578 4,229,489 10/1980 Chiu et al. ........................... 426/578 75) Inventor: Paolo C. Trubiano, Somerville, N.J. 4,281, l l l 7/1981 Hunt et al. ..... ... 426A578 73) Assignee: National Starch and Chemical 4,303,451 12/1981 Seidel et al. ........................ 426/578 Corporation, Bridgewater, N.J. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 286,411 2062459 5/1981 United Kingdom ................ 536/102 22 Filed: Jul. 24, 1981 2078767 1/1982 United Kingdom ................ 536/102 51 Int. Cl. ........................ A61K 47/00; C13L 1/00; Primary Examiner-Ronald W. Griffin CO8B 31/OO Attorney, Agent, or Firm-Edwin M. Szala; Margaret B. (52) U.S. Cl. .................................... 536/106; 106/210; Kelley 106/213; 424/361; 426/578 57 ABSTRACT (58) Field of Search ................ 426/578; 106/210, 213; Starches useful as tablet disintegrants consist essentially 424/361; 536/102, 106 of a free-flowing, crosslinked and pregelatinized starch (56) References Cited powder having a moisture content of about 12% by U.S. PATENT DOCUMENTS weight or less. The starch is characterized by its uni 2,884,412 4/1959 Neukon .............................. 106/210 formly swollen, virtually non-birefringent granules, by 3,034,91 5/1962 McKee et al. ... 106/210 a swelling value in cold water of above 3 ml. and below 3,181,998 5/1965 Kanig ............ ..... 67/82 25 mi., and by an acid viscosity breakdown of 400 B.U. 3,293,132 12/1966 Stoyle et al. .. ..... 167/82 or less, all of which are correlated to this disintegration 3,490,742 1/1970 Nichols et al. ........................ 252A99 performance. The better starch disintegrants (i.e. the 3,584, 114 6/1971 Cavalli et al. ..... ..... 424/38 more highly crosslinked) have swelling values of 18 ml. 3,622,677 11/1971 Short et al. ....... ... 424/361 3,725,556 4/1973 Hanssen et al. ... ... 424/357 or less and show little or no breakdown (0-150 B.U.). 4,072,535 2/1978 Short et al. ... ... 106/210 The modified starches may be used in any tabletting 4, 104,212 8/1978 Bruner ................................ 260/17.3 method (e.g. direct compression or granulation), typi 4, 104,213 8/1978 Chiang et al....................... 260/17.3 cally in amounts of about 10% by weight or less. 4, 183,969 M1980 Rubens .......... ... 426/578 4,207,355 6/1980 Chiu et al. ........................... 426/578 12 Claims, No Drawings 4,369,308 1. 2 swelling, cold-water-soluble intact granular starches LOW. SWELLING STARCHES AS TABLET such as starch phosphate, starch sulfate, and carboxy DSNTEGRANTS methyl starch (see U.S. Pat. No. 3,034,911 issued May 15, 1962 to I. K. McKee et al.). Physical modification by BACKGROUND OF THE INVENTION 5 compaction, with or without the use of supplemental This invention relates to low swelling starches suit thermal energy, has produced partially cold-water able for use as tablet disintegrants. It also relates to a swelling, cold-water-soluble starches which are claimed method for preparing and characterizing suitable starch to be useful as binder-disintegrants for direct compres powders. It further relates to compressed tablets con sion tabletting (see respectively U.S. Pat. Nos. 3,622,677 taining the starch disintegrants and to methods for pre O and 4,072,535 issued Nov. 23, 1971 and Feb. 7, 1978 to paring the tablets by wet granulation, dry granulation, R. W. P. Short et al.). This physical modification dis or direct compression. rupts the granular structure and results in a mixture of Tablets usually consist of several inert materials, re birefringent and non-birefringent granules, some aggre ferred to as excipients, in addition to the active ingredi gates of birefringent and non-birefringent granules and ent which is present in amounts sufficient to accomplish 15 fragments, as well as completely solubilized starch. the desired pharmaceutical, nutritive, or chemical ef It is an object of this invention to provide modified fect. These excipients are generally classified according starches which are low swelling in cold water and to their function, such as diluents (also called bulking which are suitable for use as disintegrants in compressed agents and fillers), binders which hold the ingredients tablets prepared by any tabletting method. together, disintegrants which help the tablet to break 20 apart when placed in a fluid environment and thus re SUMMARY OF THE INVENTION lease the active ingredient, and lubricants to improve The above object is achieved by crosslinking and the release of the compressed tablet from the die and pregelatinizing, in the presence of water, a cold-water punches. In addition, the tablets may contain other insoluble, granular starch, drying the crosslinked, pre substances intended to improve the tabletting process. 25 gelatinized starch if necessary, and then pulverizing the For example, glidants are added to improve the flow dry starch so as to provide a white, free-flowing starch and anti-adhesives are added to prevent film formation powder. This modified starch powder is virtually free on the punches. Other optional ingredients may be dyes, of birefringent granules, in both the dry state as well as flavors, sweeteners, and antioxidants. in aqueous dispersions, since all of the granules have The disintegrants are added directly to the dry ingre 30 been uniformly and partially swollen during the dients when the direct compression tabletting method is pregelatinization. This controlled swelling during used. When the dry or wet granulation tabletting meth pregelatinization is made possible by treating the base ods are used, the disintegrant may be added before starch with relatively high levels of crosslinking agents. granulation (intragranularly), after granulation (extra Suitable modified starch powders are characterized by granularly), or part may be added intragranularly and 35 their non-birefringent nature, by their low swelling in part added extrangranulary. cold water, and by a maximum acid viscosity break The disintegrants currently used include native down, all of which are correlated to their disintegration starches, modified starches, gums, cellulose derivatives, performance. They should have swelling values above microcrystalline cellulose, alginates, clays, effervescent about 3 ml, and below about 25 ml, and a breakdown mixtures, and enzymes. Of these, the starches, despite (defined as the loss from peak viscosity with time) of some drawbacks, are the formulator's first choice. 400 B.U. or less. The Brabender procedure and swelling Starch as a disintegrant should not be confused with test will be described hereafter. starch as a binder or diluent since different properties The modified starch powders show rapid disintegra are required for each use. Moreover, the properties tion times in tablets prepared by both wet granulation required in a disintegrant may depend upon the tablet 45 and direct compression. This rapid disintegration is ting method used. The unmodified native starches which are useful as believed to stem from the advantageous characteristics diluents are not very effective when used as disinte of the modified starch powders, particularly the dual grants unless used at high levels (i.e. 10-20%). They action of controlled low swelling combined with swell only very slightly when exposed to water at the 50 "wicking' (i.e. capillary) ability. The novel disinte temperature found in gastric or intestinal juices. This grants do not swell to the same degree as conventional results in a slight increase in volume which eventually gelatinized starch powders which, if used as disinte weakens the forces holding the tablet together and thus grants, would swell too rapidly and form a gelatinous breaks it apart. mass or sheath on the peripheral area of the tablet The cooked non-granular starches which are satisfac 55 which then acts as a barrier and prevents further water tory as binders are not satisfactory as disintegrants. absorption by the tablet. The modified starch powders They can be cooked and added as a paste or gelatinized swell enough to bring about a significant increase in the by drum drying (drum dried starches are often referred volume of the tablets without, however, blocking the to as pregelatinized starches). The cooked or gelati porous structure of the tablet or themselves losing their nized starches do not readily disperse; they tend to wicking ability. The concurrent increase in volume and hydrate rapidly and in many cases form a tacky film on continued capillary action of the disintegrants exert a the tablet's surface, thus preventing water penetration tremendous force within the tablet and effect rapid into the tablet to aid in disintegration. disintegration. Various attempts have been made to modify the cold Compressed tablets containing the modified starch water-swelling characteristics of starches to improve 65 powders also contain an active ingredient, a binder, their disintegration properties. These have included preferably a lubricant, and optionally a diluent. They chemical and physical modification of the starch, may be prepared by any of the conventional tabletting Chemical derivatization has produced cold-water methods. In addition to their excellent disintegration 4,369,308 3 4. times, the tablets show good hardness and satisfactory latinized starches. The breakdown