Mixing Solids: Random vs Ordered Mixing, Part I
Loyd V. Allen, Jr., PhD, RPh
International Journal of Pharmaceutical Compounding
Remington: The Science and Art of Pharmacy, Twenty-second Edition
In this and the next issue of the newsletter, we will discuss time-honored "random mixing" and introduce "ordered mixing," which may be new to many, and the two methods will be compared.
Generally, random mixing in compounding pharmacy involves a shuffling-type unit operation process involving particle groups and even individual particles. Mixing is an energy-consuming process that produces a random distribution of particles. Some parameters affecting efficient mixing include:
- Particle size, shape, density, cohesiveness, hygroscopicity, hardness, and size distribution.
- Mixer speed, time, batch quantity, and movement method.
- Segregation tendency of individual components based on density difference.
Regarding mixtures, there are free-flowing mixtures, cohesive mixtures, and ordered mixtures.
Free-flowing mixtures suffer from the serious drawback of segregation of individual components during further processing in dosage form preparation. Particles can move easily and independently in a particular direction because of interparticulate forces. They should be handled with minimal shaking / bouncing, especially if not used immediately for filling capsules, etc.
Cohesive mixtures are not free flowing; the individual agglomerates of particles must be repeatedly broken down and allowed to redistribute within the system to ensure a satisfactorily mixed preparation. The extent of segregation may be less than that of free-flowing powders, but they will be more difficult to redistribute due to the formation of small agglomerates. Factors contributing to the formation of cohesive mixtures include:
- Electrostatic charges
- van der Waals forces
- Solid bridges between the particles
Ordered mixtures involve the mixing of a fine, micronized form with larger carrier particles and the small particles adhere to the large particles where they are tightly held on the surface of the carrier particles. Ordered mixtures are formed by mechanical, adhesion, or coating forces so that the ordered unit consists of a large particle and its associated adhered small particles that move as a unit within the mix. Note: Additional discussion on "ordered mixtures" will be provided in the next edition of the newsletter.
Demixing, or powder segregation, is related to particle size, particle density, drug-excipient interaction, and degree of agglomeration. The three primary mechanisms of segregation of powders involve percolation, vibration, and transportation.
Percolation can result from gravity causing small particles to move into voids between larger particles, due to large particle-size differences.
Vibration causes small particles to move under the larger particles that are pushed to the surface and result in separation of differently sized particles.
Transportation of particle beds with constant acceleration and deceleration results in separation. Similar changes occur when powders are poured in a pile. The heavier particles will roll to the outside while the smaller particles locate in the center of the powder pile. The shape also is important during segregation.
Mixing powders has gradually progressed from an empirical process to one that can be better controlled today to those that have an understanding of the dynamics of powder manipulation. What is desired is to move from Example 1 all the way to Example 4 and to maintain that distribution. However, something similar to examples 2 and 3 generally results. (X= Drug; 0=Diluent)
|Example 1|| Example 2|| Example 3|| Example 4|
|00000000|| X000XX00|| XX0X00XX|| X0X0X0X0|
|00000000|| 0XX000X0|| 0X00XX0X|| 0X0X0X0X|
|00000000|| 00X00XXX|| 00XX000X|| X0X0X0X0|
|0000XXXX|| 00X0XX00|| X000XX0X|| 0X0X0X0X|
|XXXXXXXX|| 00XXX0X0|| X0XX000X|| X0X0X0X0|
|XXXXXXXX|| 0XX0XX0X|| 0X00X0XX|| 0X0X0X0X|
|XXXXXXXX|| XXXXX0X0|| X00XX00X|| X0X0X0X0|
Examples two and three demonstrate why variation can occur when a powder blend is divided into individual doses. Actually, these variations can occur in the pharmaceutical industry as well as in extemporaneous compounding. This illustrates why it is important that pharmacies have standard operating procedures for mixing steps, those procedures of which should consider the different types of powdered ingredients and their characteristics.
In the next issue, we will look at "ordered mixtures" and discuss how they differ and their applications.