The Influence Of Different Polymers On The Stability Of Amorphous Solid Dispersions

Solid dispersions are a commonly application to increase solubility. It is a dispersion system that insoluble drugs disperse in one or several polymers, and used increasingly in manufacturing. The active phamarceutical ingredient (API) exist in the carrier as amorphous state, microcrystal and molecular state after become to solid dispersion, which greatly increased the drug’s solubility and dissolution rate, and so on. But at the same time, the API has a big problem:these states are instable and will transform to stable crystals easily, which will change the API’s the solubility, dissolution rate, bioavailability, preparation and their stability. So the carriers which have a major role in the inhibition of crystallization had been the research focus. The effects of polymers on the API include two aspects:forming the hydrogen bond or ionic bond or enhance the glass transition temperature of the system to decelerate the molecular mobily. The pupose of the article is to establish a method of screening the carrier in the solid dispersion.The model drug was acetaminophen and solid dispersions were prepared using the polyethylene glycol 6000 (PEG 6000), the polymers polyvinylpyrrolidone k-30 ( PVP k-30), polyacrylic acid (PAA), Poly ally ammonium hydrochloride (PAH) and Eudragit(?) 100 (E100) and the carriers by a rotation evaporating method. The study in the chapter 1 is about the effect of different polymers on the formation of amorphous structure. The amount of the carrier that turning the crystals to amorphous solid is different, because the effects of the polymers with different structure on the drugs are different. The solid dispersions were characterized by X-ray diffraction, differential scanning calorimetry, FT-infrared spectroscopy and Polarized light hot stage microscope to verify the transformation of the crystal.The results showed that the ratios of the polymers to ACTA that the crystal transforms to amorphous solids was: PEG6000:ACTA=10:1, PVP k-30:ACTA=1:1, PAA:ACTA=4:1, PAH:ACTA=6:1, E100:ACTA=3:1. So the following rank order can be accepted for the crystallization inhibiting performance of the different polymers:PVP k-30> E100> PAA> PAH> PEG6000. This conclusion could be explicated by the polymers’ability of forming hydrogen bond and ionic interactions, the structure uint of the carriers and their crystalline state.The time keeping the amorphous state varies with the polymers. To study the ability inhibiting recrystallization and the way of interaction between polymers and ACTA, we imitated stress testing to invest the stability of the solid dispersions under seven different conditions. The process of recrystallization was accelerated to evaluate how the polymers kept the API stable. Solid dispersions were characterized by X-ray diffraction, differential scanning calorimetry, FT-infrared spectroscopy and Polarized light hot stage microscope. The ACTA was a hydrogen bond donors and can form solid hydrogen bond with E100 which contained a hydrogen bond acceptors to inhibit the recrystallization availably. And the system would be more stable due to that the E100 may form an ionic bond. So the inhibition of the E100 was the strongest. The PEG6000 was a semi-crystal which can induce and accelerate the recrystallization. In the PAH-ACTA system, amorphous ACTA only can stay 3hr. The order of the ability that the five polymers kept amorphous state is:PVP k-30> E100> PAA> PAH> PEG6000; That is to say, the ability of inhibition was not consisted with the ability to form amorphous state. We not only needed to analysis the structure of polymers but also evaluate their stability when we chose the carriers.The ratio of the carriers and the drug became to 15:1 in the chapter 3, ACTA recrystallized on the 5 day in the sealed bottle or in the environment of 60%RH,25 ℃. This phenomenon was consisted with the previous data which showed the PEG6000 was not appropriate to keep the state of the drug in the solid dispersion. So the amount of the PVP k-30、E100 and PAA could be increase to enhance the stability of solid dispersions in the prescribed amout.The carriers should be chose according to the structure of the drug:if the model drug contained the proton donors, it will form a firm hydrogen bond with the carrier which contained the proton acceptors. Meanwhile the characteristic of the carriers should be taken into consideration, for example, the PEG6000 that is a semi-crystaline and can induce the process of recrystallization. Moreover, the system would be more stable if the carrier can enhance the Tg of solid dispersion like E100. So the amorphous polymers should be chose as the carriers instead of semi-crystalline material when the drug need to be amorphous state. Additionally, the moisture should attract attention while using good hygroscopic polymers during the preparation and storage process.