The Role Of Crystal Addiction In The Production Of Solid Dosage Forms

Different preparation and processing methods of raw materials may lead to changes in the final crystal habit or even the crystal form, which in turn will cause differences in the physicochemical properties, biological properties and production controllability of the drug. For the study of drug crystal forms, the drug regulatory authorities of various countries have issued relevant guidelines. At the same time, research units are also putting the control of drug crystal forms in a pivotal position during the research and development process. Polymorphism is a difference in the internal accumulation of a drug molecule. We have consciously paid attention to its impact on drug safety, stability, effectiveness and even the controllability of production, and then to control the possible risks caused by its change. Then, crystal habit (Crystal Habit), it is the external characteristics of drug molecules, that is, a crystallization habit shown in the crystal shape during the spontaneous growth process of a specific crystal under normal external conditions. Under different crystallization conditions, due to the different preferential growth planes of the unit cell during the growth process, substances of the same crystal form may have different crystal shapes, such as common needle crystals, massive crystals, plate crystals, etc.

We know that the purpose of preparation research is to finally obtain a preparation product with good safety, high stability, certain therapeutic effect and sustainable production. The production of preparations is inseparable from the investigation and research on the physical properties of pharmaceutical powders, such as the compressibility, fluidity and filling performance of materials. These powder properties are also affected by drug crystal addiction. So, how does crystal habit affect the powder properties of pharmaceutical powder, and then affect the production performance of the preparation? May wish to explore the mystery of it today.

Effect Of Crystal Addiction On The Physical Properties Of Pharmaceutical Powders

1. Fluidity Of Drug Powder

The selection of the production process of solid preparations is generally wet granulation, dry granulation and powder direct compression process. The long-term selection process of the above-mentioned three solid preparations involves the mixing of materials, and the materials enter the feeder from the hopper. In these series of activities, the fluidity of the powder plays a key role. The uniformity of mixing will affect the quality of the final preparation product, such as the uniformity of content and the content of a single dose of drug; the good fluidity of powder also affects the sustainability of production.

When the force acting on the drug powder is sufficient to overcome the cohesive forces between the particles, then the powder will flow. The flow of drug powder is affected by many factors, such as particle size, particle shape, force between particles, and temperature and humidity in the environment. So how does crystal addiction affect the fluidity of the powder?
In general, spherical crystals have the best fluidity because of the smallest contact area between crystals and the corresponding reduction in the force between crystals; the surface of flaky crystals has a large number of plane contact points and shear between irregular particles. Force, so the fluidity is relatively poor. Generally speaking, drug crystals with smaller aspect ratios are more conducive to overtime processing of preparations than drug crystals with larger aspect ratios. Generally speaking, under the premise that the particle size is not much different, the flow order is: cubic particle shape (spherical, cubic) > planar particle shape (sheet, plate) > one-dimensional particle shape (needle shape).

2. Filling Property Of Drug Powder

In the production process of preparations such as tablets and capsules, the requirements for the filling properties of powder materials are essential. Usually, the evaluation indicators of the filling degree include bulk density (loose density and tapped density), filling rate, porosity, etc., and there is an intrinsic relationship between these parameters.
Bulk density refers to the mass of powder per unit filling volume under a certain filling state, which is the apparent density (kg/m3).

The bulk density refers to the natural accumulation of particles under the action of gravity (without any external force) during the accumulation process of the powder. At this time, the apparent density of the filler is called the bulk density.

The tap density is the forced particle rearrangement of the powder when it is subjected to external forces (such as vibration force, pressure) during the accumulation process, and the air in the filler is discharged. At this time, the apparent density of the filler is called the tap density.

The filling rate refers to the proportion of the particle volume to the apparent volume of the powder under a certain filling state. The porosity refers to the ratio of the volume occupied by the voids to the apparent volume of the powder in a powder filling system.

During powder processing, the formed particles are generally not spherical, but have edges and corners, and the particle size is inconsistent, and cannot form regular accumulation or completely random accumulation. The total accumulation degree of the powder has the following rules: when only gravity acts, the bulk density of the actual particles in the container will decrease with the decrease of the diameter of the container and the increase of the height of the particle layer; the filling body formed by the actual particles, its The porosity is closely related to the sphericity of the particles, and the porosity of the particles increases as the sphericity decreases. When loosely packed, the porosity of the filling body formed by angular particles is larger, and the porosity decreases if the shape of the particles is closer to spherical. In addition, the surface roughness of the particles has a great influence on the porosity of the filler. Generally, the greater the surface roughness of the particles, the greater the porosity of the filler.

3. Compressibility Of Drug Powder

Tabletability of pharmaceutical powder refers to the ability of pharmaceutical powder to tightly combine into tablets with a certain strength under different tableting pressures, and is described by the relationship between tensile strength (Tensile Strength, TS) and tableting pressure . In-depth understanding of compressibility can be studied from the influence of bonding area (Bonding Area, BA) and bonding strength (Bonding Strength, BS) on tensile strength. The bonding area is the contact area between the particles when the powder particles are pressed close to each other, and the bonding strength is the strength of the interaction force between the particles in the unit contact area. The larger the bonding area or the higher the bonding strength of the particles, the better the Better compressibility.

Due to its high economic value, the powder direct compression process can reduce drug stability problems to a certain extent, and the steps are simple and easy to operate. According to the MCS classification system, we can understand the concept of the permeability threshold value of a formulation, that is, in general, compared with excipients, the fluidity and compressibility of API are relatively poor, by adding a certain amount of excipients (due to filler Compared with the amount added, the general filler plays a greater role, that is, this auxiliary material can generally be considered as a filler) to improve its powder properties. Only the amount of auxiliary materials added can meet the requirements of subsequent processes. At this time, the amount of API corresponding to the ratio of auxiliary materials to API is the percolation threshold. However, the powder direct compression process has extremely high requirements on the powder properties of the raw material drug, especially for large-scale drugs.

Using spherical crystallization technology (Spherical Crystallization) to aggregate needle crystals into spherical shapes can not only improve fluidity, but also improve compressibility; using QESD (Quasi Emulsion Solvent Diffusion) technology on the ferulic acid system can improve the resistance Tensile strength is used to make tablets with high drug loading (99%), and the dissolution rate is also good; it is observed through an electron microscope that many pits appear on the surface of the spherical crystal, similar to a sponge-like structure, so the plasticity is better.

In the process of formulation development, the formulation developers pay great attention to the stability of the molecular crystal form of the drug in each process, and the research and control of the microscopic form of the drug powder is gradually deepening. Drug crystal habit, an important solid-state property of a drug, plays an important role in the production process of the preparation and affects the physical properties of the drug powder. How to control the consistency of crystal habit between batches and how to control it through corresponding means The crystalline form of drugs and how to prepare the crystal habit that meets the requirements of preparation production are all topics that we need to think about and study deeply.