Excipient Particle size

According to percolation theory, the effect of a reduction in the drug particle size should be similar to an increase in the excipient particle size in a binary system It may be expected that the relative particle size of the component, but not its absolute particle size, will determine the properties of the system. 

FIGURE 25 Drug percolation threshold (mean + SE) as function of drug-excipient particle size ratio employed. 

In addition, when the obtained drug percolation thresholds were plotted as a function of the drug-excipient particle size ratio of the matrices (see Figure 25), a linear relationship was found between the drug percolation threshold and the relative drug particle size [46]. These results are in agreement with the above exposed theoretical model based on percolation theory. 

Binary mixtures were prepared with varying drug contents (60, 70, 80, 90, and 95%) keeping constant the drug and excipient particle size. Table 24 gives the composition of the studied batches as well as the tablet thicknesses. The mixtures were compressed on an eccentric machine (Bonals A-300) without any further excipient. Cylindrical tablets with a mean dosage of 500 mg and a diameter of 12 mm were prepared at the maximum compression force accepted by the formulations. 

Besides surface texture, excipient particle size also plays an important role in the fine particle generation as shown by budesonide, where the highest fine particle fraction was obtained with small-sized (<32pm) lactose as the carrier. Additionally, fine particle excipients such as fine lactose or polyethylene glycol were reported to improve the performance of carrier-based protein dry powder aerosols.However, there are some cases where carriers improved total powder emission but reduced the percent of active powders in the aerosol. To be useful carriers, the excipients must be physically stable. The important physicochemical characteristics for drug carrier selection are discussed in Ref.t f... 

MUlan M, Caraballo I, Rabasco AM. The role of the drag/excipient particle size ratio in the percolation model for tablets. Pharm Res 1998 15 216-220. 

Influence of Drug and Excipient Particle Size on Critical Points... 

Different studies have investigated the influence of the particle size of the components of a formulation on their percolation threshold in inert matrices. Initially, the existence of a linear relationship between the drug particle size and the drug percolation threshold was demonstrated, but later studies showed that what really determines the drug percolation threshold is the relative drug particle size, i.e., the ratio between the mean drug and excipient particle size [86,87]. This fact can be explained according to the percolation theory since an increase in the particle size of all the components of a finite system is equivalent to a decrease in the size of the system. Therefore, in a binary... 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Ophthalmic ointments usually contain petrolatum as the base. The petrolatum is sterilized by dry heat and combined with the sterile dmg powder under aseptic conditions. Ophthalmic suspensions contain very fine (- 10 ji) particle sized soHds suspended in an aqueous vehicle. The vehicle is adjusted to isotonicity and viscosity-increasing excipients, chelating agents, and surfactants also may be needed. The aqueous vehicle in these cases is generally autoclaved and mixed with sterile dmg powder asceptically (30). 

An alternative approach aimed at reducing the segregation tendencies of medicaments and excipients involves milling the former to a small particle size and then physically absorbing it uniformly onto the surface of the larger particles of an excipient substrate. By these means ordered, as opposed to random, mixing is realized and dissolution is enhanced as a result of the fine dispersion [7]. 

It may sometimes by necessary to supplement the properties of the drug so that it compresses more easily, and these needs have been realized by several manufacturers of excipients. Materials described as compression aids are now commercially available. Ideally, such adjuvants should develop mechanical strength while improving, or at least not adversely affecting, release characteristics. Among the most successful at meeting both these needs have been the microcrystalline celluloses (partially acid-hydrolyzed forms of cellulose). A number of grades are available based upon particle size and distribution. 

Factors affecting the mix of active ingredients and excipients should be discussed. These should include particle size and shape, rugosity, charge, flow properties, and water content. Since the dose delivery for these products is dependent on air flow characteristics, an attempt should be made to establish an in vivo-in vitro correlation. 

The formulation of this type of product usually employs a small number of ingredients and sometimes only the active ingredient. Particle size and particle size distribution, rugosity, and particle charge should be considered for all ingredients, and the specific grade of excipients should be stated. The excipients should be sourced from a single supplier (with data to demonstrate the suitability of different batches of material), but if multiple sources are used, additional data will be required to establish the suitability of different batches from each supplier. 

Where there are existing pharmacopeial specifications for active ingredients in the Ph Eur or the pharmacopeia of a member state, these will be expected to apply. Other pharmacopeial specifications or in-house specifications may be used in other cases. The same is true for excipients where harmonized specifications are mentioned. Particular quality requirements related to a particular application are discussed, e.g., particle size control requirements. 

There are two EPARs for eyedrops. Specific issues considered for these include container composition and tamper evidence, the optimization of the formulation and manufacture, preservative and preservation issues, and justification for the use of nonterminal sterilization processes. Many of the points concerning active ingredients and excipients are similar to those discussed above. Changes in formulation during the development process (e.g., for carbomers or surfactants) are mentioned. Particle size controls for suspension products are discussed. 

Another excipient used in feed additive premixes is a diluent used to dilute or standardize activity. Diluents are similar in composition to grain carriers, except the particle size is generally smaller. No attempt is made to absorb the active drug to the individual particles of the diluents. If a liquid is used it is mainly for dust control. A diluent is considered for use when the level of the active ingredient components in the premix approaches or exceeds 50% of the product or when two or more active components vary greatly from one another in density [13]. Examples of diluent materials are ground limestone, sodium sulfate, kaolin, corn cob flour, and ground oyster shells. 

The extent of homogeneous mixing of pharmaceutical components such as active drug and excipients has been studied by near-IR spectroscopy. In an application note from NIRSystems, Inc. [47], principal component analysis and spectral matching techniques were used to develop a near-IR technique/algorithm for determination of an optimal mixture based upon spectral comparison with a standard mixture. One advantage of this technique is the use of second-derivative spectroscopy techniques to remove any slight baseline differences due to particle size variations. 

An increased rate of dissolution resulting from particle size reduction has also been observed for several excipients. For example, griseofulvin systems containing ethylcellulose of size fraction 710-850 /im released the drug almost 25% faster than the same systems containing ethylcellulose of size fraction 1000-2000 fim. The authors interpret these results in terms of more excipient particles being available to interact with the drug in the fraction of lower size [69],... 

Flow behavior of powders is also of interest in direct compression. It is generally accepted that the flow rate initially increases with particle size, achieves a maximum in the range of 100-400 /um, and then decreases [85]. An excipient that has been well characterized is lactose, which undergoes particle fragmentation when compacted. For a-lactose monohydrate, it has been shown that the... 

Many surface area studies have investigated various properties of excipients. The relationship between excipient grades, flow properties, particle sizes, and surface areas have been studied. Fast-flo lactose is manufactured to contain larger particles (approximately 50 jim) than hydrous lactose (approximately 20 /zm) [23], This has been done to improve the flow properties of the fast-flo... 

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