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Ashish A. Joshi, PH.D. and Sergio Neves PH.D.
Reproduced courtesy of Pharmaceutical Formulation & Quality magazine
Obtained from renewable resources, starch is one of the most commonly used excipients in a variety of pharmaceutical formulations. A natural polymer composed of amylose and amylopectin homopolymers of glucose, native starch is routinely used as filler, binder and disintegrant in various solid dosage forms. Although these classical functionalities of native starches vary with their source of origin, starches can be modified to fit a variety of specialized applications, making it a valuable starting material for many other interesting excipients.
Starch manufacturers have utilized various physical, chemical and biotechnological means to convert native starches into specialized derivatives, providing benefits such as improved binding (pregelatinized starch), direct compressibility (mannitol, sorbitol), encapsulation (cyclodextrins), rapid disintegration (sodium starch glycolate), sugar-free applications (maltitol, xylitol) and parenteral applications (hydroxyethyl starch, pyrogen free dextrose and polyols).
Catering to the needs of an ever-expanding pharmaceutical market, starch manufacturers continue to innovate beyond the existing starch derivatives, resulting in the development of added functionality excipients (AFEs). A single AFE provides multiple functionalities such as direct compressibility, fast disintegration, excellent flowability, reduced lubricant requirements or advantages in roller compaction and dry granulation. AFEs also provide the added value of avoiding lengthy regulatory issues that arise when new functionalities are sought with new untested molecules. This article will examine the role of some starch-based AFEs with reference to their functional properties.
Pregelatinized Starch
Native starch can be chemically and/or mechanically processed to rupture (gelatinize) all or part of the starch granules. These pregelatinized starches (PGS) exhibit good flow, binding, and compressibility. The degree of starch gelatinization can be varied to obtain fully pregelatinized or partially pregelatinized starches (PPS). PPS are used as fillers in hard gelatin capsules (5 to 75 percent), binders in wet granulation (5 to 20 percent), tablet disintegrants (5 to 10 percent), and direct compression. When used in filling hard capsules, some of the disadvantages of existing PPS include increased dust generation during processing and slow dissolution of actives from formulations.
Depending on the process of gelatinization and the composition of native starch employed, a significant variation is observed in the matrix structure of the PPS. As seen in the scanning electron micrograph (SEM) pictures, PPS particles can either exhibit a compact embedded matrix (less friable) or a loosely associated matrix (more friable) structure (Figure 1). The compact matrix PPS is more resistant to shear and hence exhibits low particle friability. A combination of decreased friability and stringent particle size control in the compact matrix PPS ensures reduced level of fine particles (Figure 2). This imparts excellent flowability and reduces dust generation during capsule filling or tableting (Table 1).
The unique characteristics of compact matrix PPS also have a favorable effect on the dissolution kinetics of the final dosage form. Capsules prepared using compact matrix PPS filler and a slow-dissolving drug such as acetaminophen exhibit faster drug dissolution compared to similar capsules prepared using loosely associated matrix PPS filler (Figure 3). The compact matrix PPS exhibits low cold-water solubility (8 percent) due to the use of an optimal combination of amylose and amylopectin containing native starches during manufacturing. Low solubilization of the PPS minimizes gelation upon contact with water and hence reduced resistance to drug dissolution. Interestingly, the rapid dissolution of acetaminophen in presence of compact matrix PPS also occurs in a pH-independent fashion.
Rapid, pH-independent drug dissolution is advantageous as according to the FDA’s Center for Drug Evaluation and Research (CDER) guidelines, it may qualify a new formulation for biowaiver on clinical testing requirements.
Added Functionality
Besides altering the processing and composition of an existing excipient, AFEs can also be obtained by co-processing two or more commonly used excipients. A combination of native starch and lactose has been commonly used in the production of tablets for a long time due to the easy availability of these high quality excipients. Crystalline lactose monohydrate provides good filler or diluent properties whereas native starch functions as an efficient tablet disintegrant.
However, none of these two excipients possess the necessary combined properties to meet the requirements of fast tablet compression lines, where problems of poor flow and segregation are critical. Lactose monohydrate provides insufficient disintegration ability whereas native starch is not well adapted for use in tableting due to its fine particle size, poor flow, elastic deformation and the tendency to generate dust.
Thus the efficient combination of starch and lactose for tableting requires the use of an elaborate and time consuming wet granulation process. In the past decade, there has been a recognized trend of avoiding such wet granulation processes whenever possible and an increased focus on the development of directly compressible formulations.
Wet Granulation, Direct Compression and More
In the case of starch lactose combination, marketed at StarLac, there has been a recent development with an added-functionality, co-processed combination of native cornstarch and a-Lactose monohydrate. As with other co-processed excipient developments, the original idea for the development of this excipient was to allow simplification of the formulation and production operation with the
development of a Direct Compression (DC) product.
However in many formulations, this co-processed AFE besides enabling DC tableting has also proven to be quite unique by generating new synergies and added advantages for the formulator. One type is a co-processed combination of 85 percent a-lactose monohydrate and 15 percent native cornstarch, obtained by spray-agglomeration of starch and lactose in purified water without using any other additives or binders. As seen in the SEM pictures, its particles exhibit a uniform spherical shape with the starch embedded in a matrix of predominantly crystalline a-lactose monohydrate (Figure 4). The compact, spherical nature of particles account for its excellent flow-properties as well as low particle friability and good shear stability, evidenced by no changes in the particle size distribution even after 25 minutes of dry mixing.(See Figure 5).
Thus, the lactose monohydrate-cornstarch mixture exhibits excellent direct compression ability (3, 4) similar to that of spray-dried lactose and may also be used in the replacement of spray-dried lactose in DC tableting (Figure 6). It also offers the added advantage of rapid tablet disintegration compared to plain spray-dried lactose tablets.
The ability to produce starch-lactose tablets by direct compression without the need for wet-granulation is of special significance in the generic pharmaceutical industry where a large proportion of tablet formulations still utilize a wet granulated combination of starch and lactose. Switching to DC tableting by the use of the lactose monohydrate and cornstarch compound may allow shortening product development and tablet processing time with a consequent reduction in the product launch time and eventual cost savings.
Rapid Tablet Disintegration
The co-processing and intimate association of starch and lactose allows the starch to be available as an efficient disintegrant. As seen in Figure 7, tablets with hardness ranging from 40 to 120N exhibit a rapid disintegration time of 15 to 23 seconds. Also, the tablets do not exhibit a significant variation in the disintegration time with increasing hardness. Changes in the levels of lubricant used during tableting also do not seem to affect the tablet disintegration time. This shows that it maintains the porosity of the tablets and the
presence of starch allows rapid tablet disintegration irrespective of tablet hardness.
Many tablet formulations specifically use expensive superdisintegrants to achieve the required tablet disintegration time. As seen in Figure 8, the tablet disintegration time with lactose monohydrate-cornstarch is almost very similar to that obtained by using additional super-disintegrants in the formula. Using this mixture may thus allow formulators to reduce or even eliminate the need for expensive super-disintegrants in their formulations. Besides the switch from wet granulation to direct compression, this reduction/elimination of super-disintegrant use in tablet formulations presents an additional aspect of cost-savings associated with its use in solid dosage forms.
Functionality Beyond Tableting
As mentioned above, the excipient alternative offers various advantages in direct
compression tableting including:
• Enhanced binding capacity and compressibility due to intimate association of the binding starch with lactose crystals;
• Excellent flow properties due to uniform particle size and no segregation;
• Rapid tablet disintegration without super-disintegrants and reduced lubricant sensitivity.
Besides these advantages, it also provides excellent grit-free, creamy texture and mouth feel for chewable or soft-chew tablet applications. It has also been found to be useful in hard gelatin capsule filling applications as an all-in-one combination of filler and disintegrant. Also it does not exhibit any interaction with the gelatin (cross-linking), which may reduce capsule disintegration time.
Recent studies have also shown the lactose monohydrate-cornstarch mixture to be an extremely efficient excipient for use in roller compaction. Compared to microcrystalline cellulose (MCC), it has been found to generate less dust during milling of the roller compacted ribbons. This reduces problems of dust-control and ensures excellent flow of granules during the tableting step. Even during the final tableting step, it retains more compressibility compared to MCC, making it a very attractive excipient for roller compaction.
Over the decades, starch has proven itself to be a highly resourceful excipient. Although considered as a traditional excipient and trusted through many years of use, it has also been the source of a variety of complex excipient derivatives in the past. Thanks to the expertise and persistence of excipient developers, various starch-based AFE’s are now being developed. With the development of such AFE’s, starch continues to be used as an integral building block for highly innovative and functional pharmaceutical excipients in order to meet the needs of an ever-demanding pharmaceutical industry.
Authors: Ashish A. Joshi is project coordinator (Pharma/Nutra) for Roquette America Inc.
Sergio Neves is director of Development and Marketing, Pharmaceutical & Cosmetics Business Unit for Roquette Frères.
For further information contact
ashish.joshi@roquette.com
Tel: 319 526 2219
sergio.neves@roquette.com
Tel: + 33 3 21 63 37 03
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