Compressibilities formulations

The effect of particle size, and hence dispersion, on the coloring properties of aluminum lake dyes has been studied through quantitative measurement of color in compressed formulations [47], It was found that reduction in the particle size for the input lake material resulted in an increase in color strength, and that particles of submicron size contributed greatly to the observed effects. Analysis of the formulations using the parameters of the 1931 CIE system could only lead to a qualitative estimation of the effects, but use of the 1976 CIEL m v system provided a superior evaluation of the trends. With the latter system, the effects of dispersion on hue, chroma, lightness, and total color differences were quantitatively related to human visual perception. 

Ferrero, C., Munoz, N., Velasco, M.V., Munoz-Ruiz, A., and Jimemez-Castellanos, M.R., Disintegrating efficiency of croscarmellose sodium in a direct compression formulation, Int. J. Pharm., 147 11-21 (1997). 

In pharmaceutical applications, sorbitol is used as a tablet diluent in wet granulation or dry compression formulations. It is commonly used in chewable tablets because of its sweet taste, and it is also used as a plasticizer for gelatin in capsule formulations. Sorbitol is utilized in sugar-free liquid preparations and as a stabilizer for drug, vitamin, and antacid suspensions. When it is used in syrups, crystallization around bottle caps is prevented. 

Because particle size is so intimately intertwined with powder performance, it is one of the prime considerations in selecting excipients to develop or improve a formulation. This is particularly important with direct compression formulations where excipient flowability and compaction performance are critical. Typically, excipients for these applications exhibit narrow size distributions with moderate-to-coarse particle size, having a mean size from 100 to 200 pm. 

All three grades of mannitol showed similar, relatively low BFI values. This low tendency for brittle fracture represents a very significant advantage of mannitol, particularly with direct compression formulations where material properties, and not powder processing, must be used alone to overcome deficiencies of the API and other ingredients. It should be remembered that low BFI is but one consideration of many when selecting excipients for direct compression formulations. 

In the steady stagnation-flow formulation the thermodymanic pressure may be assumed to be constant and treated as a specified parameter. The small pressure variations in the axial direction, which may be determined from the axial momentum equaiton, become decoupled from the system of governing equations (Section 6.2). The small radial pressure variations associated with the pressure-curvature eigenvalue A are also presumed to be negligible. While this formulation works very well for the steady-state problem, it can lead to significant numerical difficulties in the transient case. A compressible formulation that retains the pressure as a dependent variable (not a fixed parameter) relieves the problem [323],... 

With the brief discussion of index, it is now possible to identify and compare some aspects of the high-index behavior of the constant-pressure and the compressible stagnation-flow equations. To understand the structure of the DAE system, it is first necessary to identify all variables that are not time differentiated (i.e., the x vector). In the constant-pressure formulation, neither the axial velocity u nor the pressure curvature A has time derivatives. By introducing the axial momentum equation, the compressible formulation introduces du/dt. To be of value in reducing the index, however, the momentum equation must be coupled to the other equations. The coupling is accomplished through pressure, which is included as a dependent variable. The variable A is not time differentiated in either formulation. 

True and bulk density An excipient (e.g., diluent) that has a similar bulk density as the drug may be selected to minimize segregation, especially with a direct compression formulation. 

The major disadvantages of dry granulation are the reduction in tablet compressibility, formulation-dependent process optimization, and inconsistency of equipment types with respect to the process parameters being measured (e.g., roll force vs roll pressure), thus complicating transfer between equipment types. In spite of these... 

The first direct compression excipient, spray-dried lactose, was introduced in the early 1960s as a filler specifically designed for direct compression processes. Over many years, more direct compression API and excipients, especially diluents and binders, were developed. Since these are now commercially available, design of direct compression formulations is readily possible. However, despite the simplicity of the direct compression process, the pharmaceutical industry still produces most tablets by wet granulation methods.1... 

This chapter discusses key considerations in excipient selection formulation and process design and control and blending and content uniformity during development of a low-dose direct compression formulation. 

Lubrication is an important unit operation in manufacturing solid oral dosage forms, particularly when using a direct compression platform. Pharmaceutical lubricants can have a significant impact on product performance (e.g., disintegration and dissolution) as well as manufacturability. Lubrication is one of the most critical aspects of a tablet formulation. A lubricant is intended to reduce the friction between the tablet surface and die wall during and after compaction to enable easy ejection of the tablet. In low-dose dmg product development, three issues are associated with lubricating a direct compression formulation ... 

Generally, when developing a direct compression formulation, efforts to match particle size distribution and density of drug substance to the major excipients help minimize segregation. Meanwhile, the particle size distribution should be relatively narrow (100 im range) to ensure a satisfactory flow for the blend. The commonly used excipients for preparing direct compression blends can be categorized by the... 

Microcrystalline cellulose is one of the most commonly used filler-binders in direct compression formulations because it provides good binding properties as a dry binder, excellent compactibility, and a high dilution potential. It also contributes good disintegration and lubrication characteristics to direct compression formulas. When compressed, microcrystalline cellulose undergoes plastic deformation. The acid hydrolysis portion of the production process introduces slip planes and dislocations into the material. Slip planes, dislocations, and the small size of the individual crystals aid in the plastic flow that takes place. The spray-dried particle itself, which has a higher porosity compared with the absolute porosity of cellulose, also deforms... 

Microcrystalline cellulose is the most compressible of any direct compression excipient. Producing a tablet of a given hardness requires less compression force for other materials. Therefore, it is usually mixed with another filler to achieve ideal compactibility and flowability of a direct compression formulation. Large particle size grades of microcrystalline cellulose are made by spray-dried processes to form dry and porous particle surfaces. The porous surfaces provide adsorption sites needed for fine dmg particles in low-dose formulations. However, microcrystalline cellulose contains trace amounts of peroxides that may lead to chemical incompatibility with oxidatively sensitive dmg substances.34... 

A direct compression formulation should form a strong compact that can withstand coating, storage, and transportation requirements. An optimum formulation can be... 

As discussed earlier, lubrication of direct compression formulations is one of the more complex and difficult problems faced by a pharmaceutical scientist. The ideal lubrication operation provides the mildest mixing conditions that guarantee sufficient homogeneity of the lubricant. Magnesium stearate, provided as a finely divided powder, is one of the most widely used lubricants in the pharmaceutical industry. Many formulations are sensitive to the lubrication process when the formulation uses magnesium stearate powder. 

Diluents for direct compression formulations are often subject to prior processing to improve flowability and compression, for example, amorphous lactose, but this can contribute to reduced stability especially under high-humidity conditions when reversion to the crystalline form is more likely [6]. 

Microcrystalline cellulose (Avicel) is purified partially depolymerized cellulose, prepared by treating a-cellulose with mineral acids. In addition to being used as a filler, it is also used as dry binder and disintegrant in tablet formulations. Depending on the preparation conditions, it can be produced with a variety of technical specifications depending on particle size and crystallinity. It is often used as an excipient in direct compression formulations but can also be incorporated as a diluent for tablets prepared by wet granulation, as a filler for capsules and for the production of spheres. 

Diluents, although commonly presumed inert, do have the ability to influence the stability or bioavailability of the dosage form. For example, dibasic calcium phosphate (both anhydrous and dihydrate forms) is the most common inorganic salt used as a filler-binder for direct compression. It is particularly useful in vitamin products as a source of both calcium and phosphorous. Milled material is typically used in wet-granulated or roller-compacted formulations. The coarse-grade material is typically used in direct compression formulations. It is insoluble in water, but its surface is alkaline and it is therefore incompatible with drugs sensitive to alkaline pFI. Additionally, it may interfere with the absorption of tetracyclines [7]. 

In direct-compression formulation, there is a wide particle size distribution. Usually, the active drug is at the fine end of the range. Such a wide particle size range can easily result in significant segregation. Five primary mechanisms are responsible for most particle segregation problems [13]. Of these, only three typically occur with pharmaceutical powders sifting, entrainment of air, and entrainment of particles in an air stream. 

Milling can affect the adsorption of actives on the carrier surface by altering the surface properties of excipients. It was noticed that milled actives frequently failed blend uniformity criteria, but unmilled active batches consistently met the blend uniformity criteria. By adding lubricant magnesium stearate, the blending content uniformity of the milled batches can be significantly improved. A small amount of amorphous materials could affect the blending characteristics of a direct compression formulation. ... 

A growing interest in direct compression formulas has developed, mainly for economic reasons. The number of processing steps has been reduced, and the availability of many direct compression materials allows for a simplified tablet formulation. Direct compression formulations require blending only therefore, lakes and other pigments are used because the elimination... 

Tablet properties inputs) Dose (mg) Solubility Particle size (gm) Minimum bulk density (g mU ) Tapped bulk density (g mU ) Carr s compressibility (%) Formulation 50.0 Insoluble 5.0 0.4 0.7 42.857 ...

Borerro, J.M. Munoz Ruiz, A.J. Jim6nez-Castellanos, M.R. Relationship between the flow characteristics and the intrinsic factors of chlorpromazine hydrochloride and its mixtures with diluents as direct compression formulations. Boll. Chim. Earmaceutico. Anno. 1994, 755 (5), 294-300. 

A number of starch modifications are used in pharmaceutical applications. Pregelatinized or compressible starch has been chemically or mechanically processed to rupture all or part of the granules in water. It is then dried to yield an excipient material suitable for direct-compression formulations. Sterilizable maize starch contains magnesium oxide (not greater than 2.2%) and has been chemically or physically treated to prevent gelatinization on exposure to moisture or steam sterilization. Soluble starch results when potato or maize starch has been chemically treated to destroy the gelatinizing ability of starch. 

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