For a long time, the poor solubility and low bioavailability of APIhave been a major problem for drug developers, and the low solubility has led to the limitation of its formulation development form, which has brought great challenges to formulation researchers, and of course, it will also greatly affect the clinical efficacy and severely limit its further development and clinical application. As a preparation research and development personnel, it is necessary to do everything possible to use the means of preparation to turn the impossible into possible, or to use new technologies, new excipients, new equipment. The rise of nanotechnology has brought dawn to the development of poorly soluble drugs, combining nanotechnology with pharmacy, thus deriving nanomedicines, that is, drug-loaded nanoparticles with a particle size of 1~1,000 nm made of drugs and excipients (such as nanoparticles, nanoliposomes, nanoemulsions) or drug nanocrystals (that is, the nano-drug itself). Drug-loaded nanoparticles refer to the encapsulation or adsorption of drugs in carriers (carriers can be liposomes, nanogold, micelles, etc.), and the preparation process of this method is relatively complex, and there are problems such as low drug loading and poor stability. The drug nanocrystallography technology is a pure drug nano colloidal dispersion system, the drug itself is nano, does not require carrier material loading, the preparation process is simple, and the drug loading capacity is high. In the past 30 years, nanocrystalline technology has made great progress in the field of pharmacy, and the preparation technology has been continuously upgraded and updated, according to domestic and foreign reports, a variety of nanocrystals have been widely used in clinical practice, such as anticancer drugs, antifungal drugs, hormone drugs, anti-inflammatory drugs, etc., and as an intermediate preparation technology can act on a variety of delivery forms, such as oral, gastrointestinal administration, pulmonary administration, injection and ocular administration.
Nanocrystalline technology provides a feasible technical approach to improve the delivery of poorly soluble drugs. This technology reduces the particle size of the drug to the nano level, and when the drug exists in nano size, changing the properties of the drug can also undergo earth-shaking changes, which can effectively improve the solubility and dissolution rate of poorly soluble drugs, reduce the dosing volume, reduce the toxic side effects, and thus improve the bioavailability and clinical efficacy. However, the reduction of the particle size of nanocrystalline drugs brings a major problem, that is, the particles with small particle size are in a high-energy state, the surface free energy increases, and the particles will aggregate with each other. At the same time, the strong Brownian motion of nanoparticles exacerbates the continuous collision between the particles, accelerating the possibility of aggregation, agglomeration, crystal growth or transcrystallization, so one or more stabilizers (crystal growth inhibitors) are added in the process of preparing nanocrystals. Some commonly used stabilizers include: povidone, phospholipids, polysorbates, poloxamer, cellulose, or anionic surfactants. The mechanism of action of stabilizers is mainly through electrostatic repulsion between ions or spatial barriers, so as to maintain the stability of the nanosystem.
For example, in the preparation of ibuprofen nanocrystalline preparations, SDS was selected as the ion stabilizer, and polymer excipients such as HPC, HPMC-AS, PVP K30, and PVP VA64 were used as spatial stabilizers to investigate the effects of different groups of stabilizers on the particle size of the products. The results showed that HPC was the best particle size stabilization agent as a spatial stabilizer, so HPC-SDS was selected as the combination stabilizer.
Preparation method of nanocrystalline drugs
There are two main preparation methods for nanocrystals: Bottom up and Top Down. The Top Down method, also known as the dispersion method, is to disperse and reduce the particle size of the drug by means of mechanical forces such as grinding or homogenization. It mainly includes medium grinding method and high-pressure homogenization method. This method has good process reproducibility, is easy to scale up and further industrialize, and is a common means for nanocrystal preparation.
Top-down medium grinding method
The medium grinding method can be divided into two types: wet grinding and dry grinding. Wet grinding is to mix polymer materials such as drugs and stabilizers in water according to the prescribed amount, and then add them to the medium grinder, and the grinding medium needs to be added to the medium grinder in advance (the grinding medium is generally steel beads, glass beads, ceramic beads, zirconia, agate, etc.), after the instrument is started, with the help of drug particles, grinding medium and the wall of the device to produce a strong mutual collision and shear force, so that the particle size of the solid particles gradually decreases to the nanometer level, when the particle size is smaller than the size of the filter screen gap of the grinding chamber separator, The centrifugal force will be extruded out of the grinding chamber into the material cylinder, and the change of particle size will be monitored in real time at certain intervals, and if the requirements are not met, the cycle grinding will be repeated until the particle size reaches the required requirements. Dry grinding is the direct dry mixing of drugs and stabilizers to obtain nanocrystals of the desired particle size. One of the major disadvantages of dry grinding is that it is easy to cause dust and adhesive walls in the preparation process, which is not conducive to industrialization. The nanocrystalline drugs prepared by wet grinding are stable and easy to carry out the next post-processing.
Generally speaking, the key material attributes CMA (API concentration, API initial particle size, type and amount of stabilizer), key process attributes CPP (material of grinding medium, particle size of beads, flow rate of material circulation, cycle time, feed volume, temperature) will have a certain impact on the key quality attributes of nanocrystals (particle size distribution and change, physical stability, crystal form, ζ potential, chemical stability), etc., so in the preparation process, it is necessary to monitor the possible changes of these parameters in real time. It is beneficial to prepare stable nanocrystalline drugs with required particle size. Generally, in the preparation process, the appropriate API concentration is selected, the initial particle size of the API is reduced as much as possible, the appropriate stabilizer and amount are selected, the bead particle size is selected reasonably (the smaller the bead particle size, the more the number and contact points under the same weight, the higher the collision frequency, the better the grinding effect), and the rotation speed is set reasonably (the higher the rotation speed, the faster the particle movement, the higher the grinding efficiency), and the ideal nanocrystalline drug can be prepared by controlling these conditions.
For example, in the preparation of ibuprofen nanocrystals, the effects of three different specifications of zirconia beads (d=1.00, 0.65, 0.30mm) on the grinding effect were investigated. With the extension of the grinding time, the particle size trend of the three specifications flattened, and the minimum particle size of the grinding system was almost reached in 60 minutes. When 0.3mm grinding beads are selected, a smaller particle size can be achieved in a shorter time, so 0.3mm grinding beads are selected as the grinding medium.
Top-down high pressure homogenization
This method is considered to be the second most commonly used technique for nanocrystalline drug preparation. The principle of this method is that the API+ stabilizer suspension is introduced by the high-pressure pump into the homogenization valve with adjustable gaps, and the instantaneous loss of pressure material is sprayed out at a very high flow rate, and collides on the collision ring of one of the valve components, resulting in the three major effects of high-speed shearing, impact and cavitation, so as to achieve the effect of refinement and homogenization. The nanocrystalline drugs prepared by this method have small particle size, narrow particle size distribution, and good reproducibility. The key material attributes CMA (initial particle size, API concentration, stabilizer type and dosage, etc.) and the key process attributes CPP (homogenization pressure, number of cycles) will directly affect the quality attributes of nanocrystalline drugs, and may affect the particle size, ζ point, crystal form, and dissolution results of the final nanocrystals.
Bottom-up method
Also known as the anti-solvent precipitation method, the drug is first dissolved in a good solvent, and then added to another miscible bad solvent, through the change of solvent to make the drug concentration supersaturated and precipitated, by controlling the rate of crystal nucleus formation and growth to obtain nano-sized nano-drug crystals. The preparation process of this method is simple, the experimental cost is low, and the process is easy to process, but the disadvantages are also obvious, and the organic solvent is used in the test process, which is easy to cause the toxicity problem of organic solvent residue. In this method, the induction of nucleus formation and growth is a key rate-limiting step in the crystallization process.
The preparation of nanocrystalline
The nanocrystalline drug prepared by the Bottomup or Top Down method is only a formulation intermediate, which often exists in liquid form after preparation, and we need to further process it into an oral solid dosage (tablet or capsule), which is aimed at improving the stability of the drug, improving the patient’s medication compliance and treatment efficacy. Therefore, how to effectively transform it into commonly used tablet or capsule dosage forms is a difficult problem in research and development.
In order to develop an ideal tablet or capsule dosage form, the premise is to ensure that the nanocrystalline intermediates maintain good physical and chemical stability: the nanocrystalline intermediates must ensure that the particle size remains unchanged and the narrower the particle size distribution for a certain period of time, the better. And in the process of preparation and the time after the completion of preparation, there are controllable content and impurities. The good physical and chemical stability of nanocrystal intermediates can be ensured to the greatest extent by controlling the prescription screening of stabilizers, controlling the process parameters and cooling efficiency of nanocrystalline preparation, and controlling the compatibility study of excipients and APIs in the early stage of innovative drug development.
Next, how to successfully convert nanocrystalline intermediates into stable solid dosage forms? Spray drying, fluidized bed-top spray granulation and coating techniques are commonly used. First of all, nanocrystalline drugs are mostly suspension intermediates with high drug loading, and a large number of excipients are added to ensure their physical stability, so the viscosity and solid content are high. The high proportion of weight gain makes the process time-consuming and the parameters vary greatly. Secondly, if fluidized bed wet granulation is chosen, it may cause the aggregation of nanocrystalline drugs when wet, affecting the particle size, etc. If dry granulation is chosen, improper pressure of the pressure wheel may also change the structure of the nanoparticles, and if it is made into tablets, the pressure adjustment of the tablet press will not affect the crystal structure…… In order to avoid the impact of tablet pressure on the crystal, some products will choose particle capsule filling to reduce the impact of pressure on nanoparticles, and some products will wrap nanocrystalline intermediates on the surface of the blank core in the form of coating to completely avoid the generation of pressure. Therefore, in the early stage of research and development, it is still as detailed as possible to explore the preparation prescription process, including key material attributes, key process parameters, and key quality attributes to do detailed investigation and exploration, which undoubtedly increases the workload of R & D personnel, but there is no way back, and preparation R & D personnel can only pick up the burden and work hard to open up the road, and will eventually break through the encirclement and usher in the dawn of victory.
For example, in the study of the preparation of ibuprofen crystals, 0.2 gAPI, raw materials and excipients were put into 900ml of pH1.2, 4.5 and 7.2 media to investigate the dissolution curves, and the results showed that in PH7.2 medium, nanocrystals could be completely dissolved within 10 min, while raw materials and API were only 60.4% and 30.7% dissolved within 2 hours, respectively, which further indicated that the optimization and reduction of particle size could enhance the solubility of the drug and increase the dissolution rate.
In summary, although nanocrystalline technology can effectively improve the solubility of drugs, improve the bioavailability of patients, and has very broad development prospects, it must be realized that the technology is not yet fully mature, and there are still places to be improved, for example, nanocrystals are in a high-energy state in gastrointestinal fluid, which is a thermodynamically unstable system, if there is no crystallization inhibitor in the prescription or the type and concentration are not selected properly, although the drug can also quickly precipitate crystals, it will quickly reduce its own energy through further aggregation and agglomeration. to reach a stable low-energy state, which is like a spring process. However, if the prescription contains a reasonable selection of polymer crystallization inhibitors, the crystallization and precipitation of the drug will be very slow, like a parachute, and the energy will drop very slowly, so as to maintain a supersaturated concentration for a long time to maintain a good homeostasis of the nanocrystalline drug. Based on this, we need to further strengthen the research on the key factors affecting the preparation and stability of nanocrystalline drugs, strive to optimize the preparation process of nanocrystals, further reduce the particle size, improve the stability of nanocrystalline drugs, and further study the relevance and safety evaluation of nanocrystalline drugs in vitro and in vivo. Of course, our ultimate goal is to return to the original intention: to improve the solubility of drugs and bring better efficacy to patients through preparations.