Improving Oral Bioavailability of Poorly Water-soluble Drugs

In the past decade, the discovery of poorly soluble drugs has prompted a continuous need to develop a new dosage form to increase the solubility of these drugs. They increase the solubility of the drug in the gastrointestinal tract by increasing the dissolution rate of the drug in the gastrointestinal tract, thereby promoting the absorption of the drug, thereby increasing the bioavailability. Solid dispersion is one of the most promising technologies to overcome the challenge of low water solubility. However, there are some limitations in the development of solid dispersions, such as the compatibility of polymers and drugs, the stability of dispersions, etc. The use of surfactants in solid dispersions can overcome these limitations. The addition of surfactants to the solid dispersion not only increases drug-polymer compatibility, but also reduces recrystallization. It also improves the wettability of the solid dispersion, thereby increasing the solubility and improving the physical stability. However, care must be taken when choosing surfactants. Surfactants can interact with the polymer to increase the recrystallization of the drug. This article discusses the types of surfactants, issues to be considered, and related parameters.

1 Introduction

In 1961, Sekiguchi and Obi first proposed using solid dispersions to increase the dissolution and oral absorption of poorly soluble drugs. Mayersohn and Gibaldi (1966) first used solid dispersions. In 1971, Chiou and Riegelman defined a solid dispersion as “a solid dispersion of one or more active ingredients in an inert carrier matrix prepared by the melt, solvent or melt-solvent method”. The Biopharmaceutical Classification System (BCS) classifies oral drugs into four categories. The use of soluble polymers to prepare solid dispersions or to convert crystalline drugs into amorphous forms has been proposed and used.

The drug can be molecularly dispersed in amorphous particles (clusters) or crystalline particles. The characteristic of the amorphous state is that there is no long-range, three-dimensional molecular order in the crystalline state. From a practical point of view, amorphous materials can be obtained in two ways: (i) by cooling the molten liquid until the molecular mobility is “frozen”, thereby producing glass; (ii) by gradually inducing defects in the crystal, Until the amorphous state is obtained.

Industrially, amorphous solid dispersions can be prepared by melting method, rapid solvent volatilization method (spray drying, vacuum drying, freeze drying) and spray solidification method. However, due to their typical soft, viscous nature and sensitivity to pressure as a cause of instability, they may not conform to traditional dosage form manufacturing processes. The salient features of solid dispersion design include rational choice of carriers, drug carrier ratio and understanding of the drug release mechanism in the matrix. Thermal stress, chemical stress and mechanical stress applied during processing can spontaneously induce the recrystallization process. In the ever-changing drug discovery model, the amorphization of drugs provides an attractive option for overcoming the solubility limitations of “difficult to release” drugs. With the understanding of the molecular level of amorphous systems, we can design systems with predictable stability and performance. Among these methods, amorphous materials are attractive because they are widely used and meet the common standards established for good formulation methods.

2 Remarkable features and advantages of Amorphous Solid Dispersion (ASD)

l ASD is widely used in acidic, basic, neutral and zwitterionic drugs.

l Minimize the requirements for APIs (active drugs) required to evaluate efficacy and safety.

l Minimize the resources required to produce pre-clinical supplies.

l Research on alternative ways to improve bioavailability.

l The drug dissolves and absorbs quickly, which may have a rapid onset of action.

l Improve exposure (improve bioavailability, faster onset, and reduce dose). Support toxicology research and clinical tools.

l Commercialization and cover-up of peculiar smell of medicines.

l Improve the drug release of ointments, creams and gels. To avoid undesirable incompatibility. In order to obtain a uniform distribution of a small amount of drug in the solid.

l Distribute liquid (up to 10%) or gaseous compounds according to the solid dose.

3 Characterization

The characteristics of amorphous solids are different from those of crystalline solids. Amorphous materials below and above the glass transition temperature are generally described as frozen solids and supercooled viscous liquids. The physical properties of amorphous solids utilize a wide range of techniques and provide several types of information.

3.1 Powder X-ray diffraction

Powder X-ray diffraction can be used to qualitatively detect long-range ordered substances. Clear diffraction peaks indicate more crystalline material. In any system, diffraction technology may be the most authoritative method to detect and quantify molecular order, while conventional, wide-angle, and small-angle diffraction techniques are all used to study order in drug-related systems. Traditional X-ray powder diffraction (also known as PXRD) can be used to quantify amorphous substances to the 5% level, and can also be used to track phase transition kinetics under temperature and environmental control. Small-angle X-ray measurement has been used to study the structure (density) changes of glassy polymers after annealing. Neutron scattering has been widely used to characterize the short-range two-dimensional order of amorphous materials.

3.2. Differential Scanning Calorimetry (DSC)

The commonly used technique for detecting the content of crystalline substances is differential scanning calorimetry (DSC). In DSC, the sample is heated at a constant heating rate and the required energy is measured. The temperature at which the thermal event occurs can be detected using DSC. Thermal events can be glass-to-rubber conversion, (re)crystallization, melting, or degradation. In addition, the melting and (re)crystallization energy can also be quantified. The melting energy can be used to detect the amount of crystals.

3.3. Solid Nuclear Magnetic Resonance (ss-NMR)

The high-resolution ss-NMR spectrum was obtained by using MAS, and the sensitivity was enhanced by cross-polarization (CP). The advantage of 13Css-NMR is that it is a non-destructive test method that can provide information about the structure of the material. As with any other one-dimensional NMR method, as long as the relaxation rate of each species in the sample, HartmanneHahn conditions and cross-polarization rate are properly studied, the integration of the CPMAS NMR signal can be directly related to the number of 13C atoms involved. In the case that the reference spectrum of a single component cannot be obtained, the defect, amorphous content or mixed phase can be quantitatively estimated by NMR based on the comparison of the integrated intensity of two separate lines in the spectrum. The method for determining the crystallinity index of microcrystalline cellulose is as follows:

CrI 1/4a=a/(a+ b)

Where’a’ is the integral of the peak between 86 and 93 ppm, and’b’ is the integral of the peak between 80 ppm and 86 ppm.

However, this type of analysis can sometimes be tricky, especially when two lines in the range overlap and are not easy to unwind. According to the expected difference in mobility between the amorphous and crystalline regions, these difficulties can be overcome by using other independent measurement methods, such as the T1 or T1r relaxation time of 1H or 13C.

3.4. Thermostat Differential Scanning Calorimetry (TMDSC)

In MTDSC, sine wave modulation is superimposed on the traditional linear (or isothermal) heating or cooling temperature program. MTDSC is based on the same theory as conventional DSC, where the heat flow signal is a combination of the sample heat capacity Cp,t (heat rate dependent component) and any temperature-dependent, usually irreversible “kinetic” component. 22 The basis of using MTDSC to quantify the amorphous content of a sample is to measure the thermal capacity jump associated with the glass transition of the amorphous phase. The method is to prepare a calibration curve based on the thermal capacity jump of a physical mixture of known crystallinity.

Cp=K (Cp) AmpMHF / AmpMHR

Among them, K(Cp) is the heat capacity constant, and AmpMHF and AmpMHR are the amplitudes of modulating heat flow and heat rate, respectively.

K(Cp) = Cp, Theoretical /Cp, measured

However, to perform accurate heat capacity measurement, factors such as the thickness of the sample bed in the sample pan, the thermal resistance between the sample and the sample pan, and the thermal resistance between the sample pan and the bottom of the instrument must be considered in order to obtain reliable results.

3.5. Inverse Gas Chromatography (IGC)

Gas chromatography (GC) is a vapor absorption technique that loads powder into a column and then injects a known vapor (usually infinitely diluted in a carrier gas). From the retention time of the probe, the surface properties of the material in the column can be evaluated. IGC is a highly sensitive technique that has been used to determine the specific adsorption energy of the polar probe DGSP A, which can then be used to calculate the basic/acidic parameter ratio Kd/Ka. This parameter describes the acidity and alkalinity of the powder surface and can be related to the degree of crystallinity. A value of 24Kd/Ka greater than 1 indicates the basicity of the solid surface, and less than 1 indicates acidity.

3.6. Dynamic Vapor Absorption (DVS)

Water absorption or gravimetric analysis technology has been widely used in the research of many amorphous and partially amorphous powders. This is a useful way to standardize amorphous components as a single component or as a combination. Dynamic Vapor Absorption (DVS) is based on the concept of using amorphous materials that change with humidity to crystallize to remove moisture. The degree of water absorption and desorption is related to the amorphous content of the sample. The working principle of DVS is to simply detect the crystalline response of amorphous materials, with little or no interference response from crystalline components. Gravimetric research is usually carried out in a humidity-controlled microbalance system. The sample is loaded on one side of a single or dual pan balance, and the system is programmed to measure adsorption and desorption at a specific humidity and temperature. However, the moisture absorption isotherm cannot be used to quantify the amorphous content, because the moisture absorbed by the amorphous area and the moisture adsorbed on the surface will contribute to the total moisture adsorbed by the sample.

3.7. Dissolution calorimetry

Dissolution calorimetry measures the dissolution energy, which depends on the crystallinity of the sample. Generally, the dissolution of crystalline substances is endothermic, while the dissolution of amorphous substances is exothermic.

3.8. Confocal Raman Spectroscopy

Confocal Raman spectroscopy is used to measure the uniformity of solid mixtures. According to description, the standard deviation of the drug content is less than 10%, which means uniform distribution. Since the pixel size is 2μm3, there is still uncertainty about the existence of nano-amorphous drug particles.

4 Preparation method of amorphous solid dispersion

4.1. Melting method

The melting method is sometimes called the melting method, and is only correct if the starting material is crystalline. The melting method is the first use of the melting method to prepare a simple eutectic mixture by Sekiguchi and Obi Leuner and Dressman (2000). The melting method is described as a hot melting method. This method involves melting the drug in the carrier, then cooling and crushing the resulting product. This process has some limitations, such as the use of high temperatures in the melting process and the possibility of drug degradation, and the incomplete compatibility between the drug and the carrier. The melting or melting method is to prepare a physical mixture of the drug and the water-soluble carrier and heat it directly until it melts. Then, the melted mixture was rapidly solidified in an ice bath under vigorous stirring. The final solid matter is crushed, crushed and sieved. Suitably, this makes many modifications when pouring a uniform melt in the form of a thin layer onto a ferrite plate or stainless steel plate and cooling by flowing air or water on the opposite side of the plate. In addition, the supersaturation of the solute or drug in the system can usually be obtained by rapidly cooling the melt from a high temperature. Under this condition, the solute molecules are retained in the solvent matrix through the instantaneous solidification process. When used in simple eutectic mixtures, the quenching technique provides finer grain dispersion.

4.2. Grinding method

These drugs were ball milled in a hybrid mill (Glen Creston Ltd., Loughborough, UK) for 120 minutes, using a 25 mL sealed chamber, 2% w/v, stainless steel ball bearings with diameters of 2e12 mm and 6e7 mm. The sample is ball milled at a speed of 17.5/s.1.

4.3. Solvent evaporation method

The solvent evaporation method is a simple method for preparing amorphous solid dispersions in which the drug and carrier are dissolved in a volatile solvent. The first step of the solvent method is to prepare a solution containing the matrix material and the drug. The second step involves removing the solvent that caused the solid dispersion to form. Mixing at the molecular level is preferred because this leads to the best dissolution performance. Using the solvent method, pharmaceutical engineers face two challenges. The first challenge is to mix the drug and the matrix in a solution at the same time, which is difficult to achieve when the polarities are significantly different. In order to minimize the particles of the drug in the solid dispersion, the drug and the matrix must be dispersed in the solvent as finely as possible, and it is preferable that the drug and the matrix material are in a dissolved state in a solution. The second challenge in the solvent method is to prevent phase separation, such as phase separation. Crystallization of the drug or matrix during the removal of the solvent.

4.4. Hot melt extrusion

Melt extrusion is basically the same as the melt method, except that the extruder causes intense mixing of the components. Compared to melting in a container, the stability and dissolution of the product are similar, but melt extrusion offers the potential to shape heated drug-matrix mixtures into implants, ophthalmic inserts or oral dosage forms. Understand the theoretical method of the melt extrusion process. Therefore, the flow process is usually divided into four parts to introduce the feeding of the extruder, the conveying of the material (mixing and reducing the particle size), the flow through the die, and the discharge from the die. And downstream processing.

4.5. Freeze drying technology

Freeze drying involves the transfer of heat and mass to and from the product being prepared. This technology is proposed as an alternative to solvent volatilization. Freeze-drying has always been considered as a molecular mixing technology. The drug and carrier are co-dissolved in a common solvent, frozen and sublimated to obtain a freeze-dried molecular dispersion.

4.6. Supercritical fluid method

In supercritical fluid anti-solvent technology, carbon dioxide is used as an anti-solvent for the solute, but it is a solvent compared to organic solvents. Different authors use different abbreviations to denote the micronization process: aerosol solvent extraction system, compressed fluid antisolvent precipitation, gas antisolvent and supercritical fluid solution enhanced dispersion, and supercritical antisolvent. The SAS process involves spraying a solution consisting of a solute and an organic solvent into a continuous supercritical phase that flows simultaneously. The use of supercritical carbon dioxide is advantageous because when the process is complete, even a small amount of carbon dioxide is trapped in the polymer, it is easier to remove from the polymer material; it does not pose a danger to the patient. This technology does not require the use of organic solvents, because carbon dioxide is considered environmentally friendly, so this technology is called “solvent-free”. This technique is called rapid expansion of supercritical solutions (RESS).

5 Conclusion

Amorphous solid dispersions are widely used in the preparation of poorly soluble drugs for oral administration. This article mainly introduces the preparation method and characterization of the dispersion. The amorphous solid minimizes the various shortcomings of the oral drug delivery system. Improving the solubility of drugs is still one of the most challenging aspects of drug development in the pharmaceutical field. Various methods have been developed to improve the solubility and dissolution of drugs. Amorphous solid dispersion is one of the most effective ways to achieve solubilization of poorly soluble drugs. Various methods for preparing ASD on laboratory scale and industrial scale are introduced.