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by modification of the manufacturing process. The small particle size and associated large specific surface area impart desirable flow characteristics that can be exploited to improve the flow properties of dry powders. Colloidal silicon dioxide is used as a glidant in tablet formulations at concentrations of 0.1-1.0% w/w [217].
A summary of the excipients that were investigated for use for the development of a NVP sustained release tablet with their respective sources and use is summarised in Table 4.1.
Table 4.1. Excipients used in NVP SR tablet formulation development
Excipient Source Use
Nevirapine Boehringer Ingelheim, USA API HPMC (Methocel® K4M,
K100M) Colorcon® LTD, Dartford,
Kent, UK Release rate control
polymer Carbomer (Carbopol® 71G
NF) Noveon®, Inc., Brecksville,
Cleveland, USA Release rate control polymer
Ammonio methacrylate
(Eudragit® RS PO) Rohm Pharma Polymers,
Darmstadt, Germany Release rate control polymer
MCC (Avicel® PH102) FMC® Biopolymer, USA Filler Spray-Dried Lactose
(SuperTab®) Lactose New Zealand Diluent Magnesium Stearate Aspen® Pharmacare, SA Lubricant DCP (Emcompress®) Penwest® Pharmaceutical Co.,
Mendel, UK Flow-aid/filler
Talc Aspen® Pharmacare, SA Glidant
Colloidal Silicon Dioxide Aspen® Pharmacare, SA Glidant
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4.3.1 Particle Size and Shape
The measurement of particle size and distribution is an important parameter that must be evaluated during preformulation studies. The safety, stability and viability of an API and dosage form during and after manufacture can be significantly influenced by this parameter [207, 217].
Furthermore, the particle size of an API and excipients can affect uniform mixing, flow and, formulation characteristics, unit to unit content uniformity, dissolution rate and the bioavailability of an API [245].
Powder characteristics such as porosity and flowability are significantly affected by the particle size of excipients and API. Therefore detailed information of the particle size of an API, excipients and other materials or blends must be ascertained prior to tablet formulation development studies. During the tableting process the particle size of a material is important as it can have an impact on the homogeneity of a powder blend and of the final tablet. The ideal size range of particles for use in tableting is between 10 and150 µm and the particle size should be as consistent as possible throughout the production process [245].
Particle size is expressed in terms of the diameter and degree of asymmetry of particles and as asymmetry increases the difficulty of expressing size in terms of diameter is compounded [246]. A powder is regarded as monodisperse if all particles in a sample are of the same size and is polydisperse, if they are of different sizes. A monodisperse particle size distribution is more desirable than a polydisperse one [245].
Good powder flow properties are required for the successful manufacture of tablets as adequate fluidity of powders is necessary to facilitate the transport of material from a blender to the hopper and onto the die table of the tablet press. Elongated particle shape and small size may result in unacceptable blend uniformity, difficulty in filling die cavities and high variability of weight and strength of tablets [245-247].
The flow of powders into orifices is important when filling the die cavity of a tableting press and the flow into or through an orifice is dependent on the particle size of the material.
Generally, as the particle size increases the powder flow rate increases up to a maximum and practically no flow occurs if the particle size of a powder is < 50 µm or > 1200 µm. Powders
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with particles < 50 µm generally exhibit irregular or no flow due to particles agglomeration as a consequence of Van der Waal’s forces [245].
The Hausner ratio (HR) and Carr compressibility index (CI) of powders provide an indication of powder flowability. The HR ranges from 1.2, for a free flowing powder, to 1.6 for a cohesive powder and the lower the CI of an excipient or powder blend the more acceptable the powder flow. The interpretation of the values of the HR and CI for powder flow is summarised in Table 4.2. The addition of a lubricant to a powder blend can significantly improve powder flow when the value of CI is above 20% [248].
Table 4.2. Interpretation of Hausner Ratio and Carr’s Index
Hausner Ratio Flow
< 1.25 Good
> 1.50 Poor
Carr Index
5-12 % Excellent
12-16 Good
81-21 Fair
23-35 Poor
33-38 Very poor
> 40 Extremely poor
The angle of repose (AOR) is another common method that is used to measure powder flow when small sample quantities of material are available. The powder to be evaluated is poured from a funnel onto a horizontal surface so as to form a cone with only gravitational force, effecting the flow. The angle between the side of the cone and the horizontal is called the AOR and is a measure of the cohesiveness of a powder as it reflects the point at which inter- particulate attraction exceeds gravitational pull on the particles in that powder. A free flowing powder will form a cone with shallow sides and therefore a small AOR, whereas a cohesive powder will form a cone with steep sides. An AOR < 30° is indicative of good flow properties whereas powders with an AOR > 40° are likely to exhibit poor flow and the addition of a glidant may improve powder flow and the manufacturing process [245, 248].
The interpretation of the AOR is listed in Table 4.3.
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Table 4.3. Interpretation of angle of repose
AOR Flow
< 25 Excellent
25 – 30 Good
30 – 40 Fair (passable)
> 40 Very poor
4.3.2 Powder Density
The volume that a powder occupies when poured into a container is dependent on a number of factors including the particle size, shape and surface properties of the material. Subjecting a powder bed to vibration or pressure will result in the particles moving relative to one another in order to improve the packing arrangement in that container, by a process termed densification. Eventually a condition is reached where further densification of the powder is not possible without particle deformation. The density of the powder is therefore dependent on the conditions to which the material has been subjected to and several definitions can be used to describe the bulk powder or the individual particles of that power [245, 248].
4.3.2.1 Bulk Density
The bulk density of a powder refers to the volume of a specific mass of powder including the particulate and pore volume. The bulk density will vary depending on the packing arrangement of the powder. The minimum bulk density is achieved when the volume occupied by the powder is at a maximum, due to aeration that is present immediately prior to complete disruption of the bulk material [245, 248].
4.3.2.2 Tapped Density
The tapped density of a powder is the maximum bulk density that can be achieved without particle deformation [245]. It is established by tapping a fixed mass of material in the container in which the aerated sample is placed. If the structure of the powder is cohesive it will collapse significantly on tapping whereas a free flowing powder has little room for further consolidation [245-247].
The bulk and tapped densities were used to calculate CI, which was used in the assessment of powder flow characteristics of the materials used in these studies.
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