A calculation method for determining purity of organic crystalline substance by DSC single peak method

Abstract

The application belongs to the technical field of instrumental analysis, and particularly relates to a calculation method for determining purity of organic crystalline substances by DSC single-peak method. T i is the temperature of the sample at t i , and the unit is K; T0 is the melting point of the pure main component obtained by extrapolation of the fitting straight line, and the unit is K; R is the ideal gas constant (8.314 J·mol ‑1 ·K ‑1 ); m is the content fraction of the sample containing impurities; △H F is the melting enthalpy (J·mol ‑1 ) of the main component, and the melting enthalpy of the impurity is set to be equal to that of the main component, and both are constant and do not change with temperature; P i is the melting absorption peak area (melting enthalpy) fraction of the sample after introducing the redistribution parameter (D R ) at t i . The calculation method provided by the application can quickly and accurately determine the purity of the organic crystalline substance.

Description

Technical Field

[0001] This invention relates to the field of instrumental analysis, and more particularly to a method for calculating the purity of organic crystalline substances using the DSC single-peak method. Background Technology

[0002] The determination of purity of organic crystalline substances by DSC was first reported in the 1960s. Its characteristics are that it does not require standard control samples, has a short measurement time, and requires a small sample amount. However, this method has some limitations and shortcomings. One of them is that the impurity content is expressed as a molar percentage. Since the molecular formula of the impurities is unknown, the results of this method cannot be accurately compared with the results expressed by mass fraction, absorption area fraction at a specified wavelength, or fractions in other units of measurement.

[0003] As a method for determining drug purity, this analytical method has been included in the United States Pharmacopeia, ASTM, the World Health Organization (WHO), and the European Pharmacopoeia. Commercially available DSC instruments fall into two main categories: one is the power-compensated DSC manufactured by PerkinElmer (PE's DSC instruction manual includes a disclaimer stating that it assumes no responsibility for the molar content results); the other is the heat-flow DSC manufactured by other instrument companies. The theoretical basis for the determination methods of both types of instruments is the Van't Hoff formula, but to date, there have been no reports of direct and rigorous proof of this basis.

[0004] Ding Enyong et al. questioned the theoretical basis of this method; Ren Wanting et al. (2010) conducted a theoretical analysis of the power-compensated DSC curve. Applying the Van't Hoff formula in thermodynamics requires the sample to meet or basically meet the three basic conditions of ideal crystal, ideal solution, and phase rule. However, to date, there are few documents that have provided direct and rigorous proof that the samples measured meet the above basic conditions.

[0005] There are several problems with the dynamic DSC method for determining the purity of organic crystalline substances and the connection between thermodynamic conditions. In addition to the most prominent problem that the sample is not in thermal equilibrium (which is incompatible with the Van't Hoff formula, which is in the thermodynamic realm), there are also the following prominent problems: without exception, the data pairs extracted from the DSC spectrum can only produce concave curves (1 / FT) when plotted. Only after linearizing a portion of the measured data pairs under certain constraints can these data pairs meet the linearity requirements of the formula. This leads to different authors holding different views on the reasons for the formation of concave curves and the rationality of the linearization scheme.

[0006] The Van't Hoff formula requires the tested sample to belong to a binary simple eutectic condensation system and to exhibit behaviors incompatible with the formula, such as non-decomposition, non-volatilization, and non-solution formation. However, many studies have reported that even for samples that do not conform to the binary simple eutectic condensation system and exhibit behaviors such as decomposition, volatilization, and solid solution formation, some data pairs can be made to conform to the linearity of the formula by correcting some of the measured data pairs, and results that are consistent or basically consistent with the comparison method can be obtained based on the formula.

[0007] To make the dynamic DSC method as close as possible to the thermodynamic and thermal equilibrium conditions, the pharmacopoeia and ASTM specify operating conditions with small sample sizes and low heating rates. However, literature reports (e.g., Zhang Wei (1993), Li Wei (2002), Wang Yanfei (2013), Zhou Jinyan (2018)) have also obtained results that are in good agreement or basically in good agreement with the comparison method under operating conditions with large sample sizes and high heating rates, after correcting some of the measured data.

[0008] Although different literature gives different reasons for the need for linearization mentioned above, the only reason that is compatible with Van't Hoff's formula is that "the instrument is not sensitive enough to detect 'early melting'", but this reason contradicts the data in practice and is probably difficult to accept.

[0009] Because the instrument is not sensitive enough to detect "early melting", the area △ / A is compensated accordingly. 总 It should be roughly equivalent to twice the impurity mol fraction. However, many literature reports data that are much higher than two times, 30 times, 17 times, 108 times, 21 times, and 424 times, which contradicts the above conclusion.

[0010] Furthermore, "the instrument is not sensitive enough to detect 'early melting,' and the compensated area △ / A" 总 It should be a positive value, but in practice it has become a negative value, thus negating the above reasoning once again.

[0011] Although numerous studies report that the results obtained under conditions conforming to the Van't Hoff formula are in good agreement with or largely in agreement with the comparison methods, most of these data only allow the expression of impurity content in mol% and cannot be accurately compared without knowing the molecular weight of the impurities. Therefore, one cannot conclude that the theoretical basis of this method is the Van't Hoff formula simply because the results obtained are in good agreement with or largely in agreement with the comparison methods.

[0012] In view of the shortcomings of the existing technology, the inventor, based on years of rich experience and professional knowledge in this field, combined with theoretical analysis and research innovation, has developed a calculation method for determining the purity of organic crystalline substances using the DSC single-peak method. This method completely abandons the Van't Hoff formula as the theoretical basis of the test method and proposes a new empirical formula, which is very suitable for the intermediate control and initial inspection of products in the production of synthetic compounds, especially in production processes where the synthesis process and raw material quality are relatively stable, the species of impurities are certain, and their content varies within a certain range. Summary of the Invention

[0013] The first objective of this invention is to provide a method for calculating the purity of organic crystalline substances using the DSC single-peak method. This method overcomes the shortcomings of the Van't Hoff formula in calculating the purity of organic crystalline substances using the DSC single-peak method. It comprehensively considers the redistribution of the melting endothermic peak area due to overlapping thermal effects during the overall melting process of the sample, avoiding the inaccuracies caused by compensating for the melting area that cannot be confirmed in the early stages of melting in traditional methods. This method enables rapid and accurate determination of the purity of organic crystalline substances and can be applied to real-time monitoring and analysis of the melting process of organic crystalline substances.

[0014] The above-mentioned technical objective of the present invention is achieved through the following technical solution:

[0015] This invention provides a method for calculating the purity of organic crystalline substances using the DSC single-peak method, employing the following formula to calculate the purity of the organic crystalline substances: T i =T0-(RT0) 2 m / ΔH F ) / P i (1)

[0016] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0017] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0018] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0019] m is the content fraction of impurities in the sample;

[0020] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0021] Furthermore, the content fraction of impurities in the sample is a mass fraction, a mol fraction, or a fraction of the area of ​​light absorption at a specified wavelength.

[0022] Furthermore, P i (P 1 i and P 2 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample). 1 R and D 2 R The area fraction of ).

[0023] Furthermore, P i The calculation formula (approximate formula) is: P 1 i =(A i +D 1 R ) / (A 总 +D 1 R ), 1 / P 1 i =(A 总 +D 1 R ) / (A i +D 1 R ); where A i From the point where the DSC curve deviates from the baseline to t i The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 1 R It is the redistribution parameter of the sample's enthalpy of melting, which is the A value of the envelope under the DSC curve. 总 The parameters for the redistribution of the area of ​​the overlapping melting endothermic peaks prior to the process of a solid phase S dissolving in a liquid phase L (SL) during the process from the start of melting to full melting of the sample.

[0024] Furthermore, the exact formula P 2 i =(A i +D 2 R ) / A 总 , 1 / P 2 i =A 总 / (A i +D 2 R A i From the point where the DSC curve deviates from the baseline to ti The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 2 R It is the redistribution parameter of the sample's enthalpy of melting, which is the A value of the envelope under the DSC curve. 总 The parameters for the redistribution of the area of ​​the overlapping melting endothermic peaks prior to the process of a solid phase S dissolving in a liquid phase L (SL) during the process from the start of melting to full melting of the sample.

[0025] This invention starts with the analysis of the DSC melting curve of the sample, fully considering the kinetic thermal hysteresis that causes the coexistence of two phases—solid phase S dissolving into liquid phase L (SL)—during the process from the initial melting to complete melting, and the redistribution of the melting endothermic peak area due to the overlap of the previously continuous "seamless" thermal effects. Formula P is then established. 2 i =(A i +D 2 R ) / A 总 To accommodate the results reported in published literature, an approximation of the above formula is given:

[0026] P 1 i =(A i +D 1 R ) / (A 总 +D 1 R Using the calculation formula: P 1 i =(A i +D 1 R ) / (A 总 +D 1 R When ), there is no compensation area △, only the area redistribution parameter D. 1 R When using equation (1), A 总 The total enthalpy of fusion is represented by the total area of ​​the envelope under the curve of the sample from the beginning of melting to complete melting.

[0027] Furthermore, P i The value of is limited to a process range in which the solid phase S dissolves in the liquid phase L (SL) and the two phases coexist.

[0028] Furthermore, the sum of D is taken within a certain temperature range and in different temperature ranges. 1 R Or D 2 RThe formula (1) corresponding to the value has a minimum value for the sum of squared residuals, provided that the correction determination coefficient is closest to 1.

[0029] For a two-component solid solution eutectic agglomerate system (sample), the melting process begins with the melting of the eutectic (S... 主组分固溶体 +S 杂质(或杂质固溶体) +L (主组分+杂质 Then, immediately following, a solid solution of the main solid component S dissolves in the liquid phase L(S). 主组分固溶体 -L) The process of two phases coexisting, the above two melting processes are continuous and "seamlessly" connected melting processes. Using the formula provided by this invention, the problem of redistribution of the melting endothermic peak area of ​​the corresponding overlapping thermal effects can be solved, so that the calculation method is more accurate, faster and simpler.

[0030] Furthermore, D 1 R Or D 2 R The value is from the A value of the DSC curve. i -T i Select T from the data column onset -T peak Partial data pairs in a data column.

[0031] Furthermore, take T onset -T peak The data column contains 8 or more data pairs.

[0032] Furthermore, the DSC single-peak method for determining the purity of organic crystalline substances provided by this invention is used to calculate samples with a total impurity content of ≤3% and a main component purity of ≥97%.

[0033] Furthermore, the calculation method provided by this invention is used to calculate samples with a total impurity content of ≤2% and a main component purity of ≥98%.

[0034] Furthermore, the formula provided by this invention is very suitable for the central control and initial inspection of products in the production of synthetic compounds, especially in production processes where the synthesis process and raw material quality are relatively stable, the species of impurities are certain, and their content varies within a certain range. Specifically, after determining the applicability and effectiveness of the empirical formula through detailed preliminary experiments, the conditions determined by the preliminary experiments can be used for routine analysis without having to compare with the comparative method for each measurement.

[0035] Furthermore, the formula provided by this invention is also applicable to the calculation of the purity of organic crystalline substances in samples that do not conform to a binary simple eutectic condensation system.

[0036] Furthermore, the formula provided by this invention is also applicable to the calculation of the purity of organic crystalline substances in some multi-component systems.

[0037] In summary, the present invention has the following beneficial effects:

[0038] This invention overcomes the defects and contradictions of the Van't Hoff formula in the calculation of the purity of organic crystalline substances by the DSC single-peak method. It comprehensively considers the redistribution of the melting endothermic peak area due to the overlapping thermal effects during the overall melting process of the sample, avoiding the need for compensation area Δ for the melting area that cannot be confirmed in the early stage of melting, which is theoretically unfounded and contradicts experimental data. This allows for the accurate determination of the purity of organic crystalline substances and can be applied to the real-time monitoring and analysis of the melting process of organic crystalline substances. Attached Figure Description

[0039] Figure 1 This is a comparison graph (1 / F'-T) of the Milrinone literature data curve (B) and the fitted line (Linear Fit of B) in Example 3 (△=0.08A). 总 (Calculated using Origin software);

[0040] Figure 2 This is a comparison chart (P) of the data curve (B) and the fitted line (Linear Fit of B) in Table 7 of Example 3. 2 ;D 2 R =0.242A 总 (Calculated using Origin software);

[0041] Figure 3 The purity determination curve and parameters of 2-fluoro-3-chlorobenzenesulfonamide in Example 4 (calculated using PE random software) are shown.

[0042] Figure 4 It is the 1 / F'-T fitted line in Example 4 (calculated by PE random software);

[0043] Figure 5 This is a comparison chart of the line connecting (B) and the fitted line (Linear FitofB) for the data intervals of 1 / F' (values ​​1-19) in Table 8 of Example 4 (1 / F'-T; Δ = 0.0121A). 总 (Calculated using Origin software);

[0044] Figure 6 This is a comparison chart of the data line (B) connecting the intervals of 1 / F' values ​​from 2 to 18 in Table 8 of Example 4 and the fitted straight line (Linear FitofB) (1 / F'-T; Δ = 0.0121A). 总 (Calculated using Origin software);

[0045] Figure 7The purity determination curve and parameters of 2-fluoro-3-chlorobenzenesulfonamide in Example 5 (calculated using PE random software);

[0046] Figure 8 It is the 1 / FT fitted straight line in Example 5 (calculated by PE random software);

[0047] Figure 9 This is a comparison chart of the data line (B) and the fitted straight line (Linear FitofB) input into the PE random software in Example 5 (calculated by Origin software);

[0048] Figure 10 The purity determination curve and parameters of 2-fluoro-3-chlorobenzenesulfonamide in Example 6 (calculated using PE random software);

[0049] Figure 11 It is the 1 / FT fitted straight line in Example 6 (calculated by PE machine software). Detailed Implementation

[0050] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the specific implementation method, features and effects of a calculation method for determining the purity of organic crystalline substances by DSC single-peak method according to the present invention are described in detail below.

[0051] Example 1: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0052] This embodiment compares the results calculated using traditional methods based on literature data (Wang Lei, Wang Lishen. Determination of drug purity by differential scanning calorimetry, Chinese Journal of Modern Applied Pharmacy, 2005, 22(6): 498-500) and empirical formulas.

[0053] In this embodiment, the instrument used is a CDR-1 differential thermal analyzer (Shanghai Balance Instrument Factory).

[0054] Table 1. Literature Data

[0055]

[0056] Table 2. Comparison of the optimized Δ from literature data (traditional method) and the calculation results from formula (1) in this embodiment.

[0057]

[0058]

[0059] The temperature range is 431.62–432.05 K, with 9 points. Degrees of freedom: 7. S x / X=((S 斜率 (slope)2 +(2×S 截距 / intercept) 2 ) 0.5 (The same applies below). S m / m=((S 斜率 (slope) 2 +(2×S 截距 / intercept) 2 ) 0.5 (The same applies below). S x / X and S m (S△H / △H) is not included in the / m item. 2 Item (the same applies below).

[0060] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔH F ) / P i (1) Calculation;

[0061] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0062] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0063] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0064] m is the content fraction of impurities in the sample;

[0065] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0066] P i (P 1 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample). 1 R The area fraction of ).

[0067] P i The formula for calculating P is: 1 i =(A i +D 1 R ) / (A 总 +D 1 R ), 1 / P1 i =(A 总 +D 1 R ) / (A i +D 1 R ); where A i From the point where the DSC curve deviates from the baseline to t i The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 1 R It is the redistribution parameter of the sample's enthalpy of melting, which is the A value of the envelope under the DSC curve. 总 The parameters for the redistribution of the area of ​​the overlapping melting endothermic peaks prior to the process of a solid phase S dissolving in a liquid phase L (SL) during the process from the start of melting to full melting of the sample.

[0068] In the formula provided in this embodiment, (P) i =P 1 i D 1 R =△) The results obtained by calculation are the same as those obtained by traditional methods for impurity content and main component purity, but the units of measurement may be the same or different.

[0069] By selecting a fitting linear formula under specified conditions, a better fitting linear formula than that obtained by traditional methods can be obtained (compare Δ = 0.08A). 总 In this embodiment, the optimized value of Δ is: Δ = 0.102A. 总 ).

[0070] Therefore, using the formula provided in this embodiment, (P i =P 1 i D 1 R =△) Calculate the fitted linear formula under specified conditions, and you can get a fitted linear formula that is better than that obtained by traditional methods.

[0071] In the calculation formula provided in this embodiment, P i You can also use P 2 i =(A i +D 2 R ) / A 总 , 1 / P 2 i =A 总 / (A i +D 2 R )Calculation; Ai From the point where the DSC curve deviates from the baseline to t i The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 2 R It is the redistribution parameter of the sample's enthalpy of melting, which is the A value of the envelope under the DSC curve. 总 The calculation results of the coexistence of two phases, namely a solid phase S dissolved in a liquid phase L (SL), during the process from the start of melting to complete melting of the sample, and the redistribution parameters of the overlapping melting endothermic peak area before this process are shown in Table 3.

[0072] Table 3.P i =P 2 i Calculation results

[0073] <![CDATA[D 2 R ]]> <![CDATA[0.101A 总 ]]> <![CDATA[0.102A 总 ]]> <![CDATA[0.103A 总 ]]> <![CDATA[0.1035A 总 ]]> <![CDATA[0.104A 总 ]]> Intercept / K 432.186 432.187 432.189 432.189 432.190 <![CDATA[SD 截距 ]]> 5.46E-03 5.47E-03 5.50E-03 5.51E-03 5.53E-03 slope -0.06797 -0.06867 -0.06936 -0.06971 -0.07006 <![CDATA[SD 斜率 ]]> 0.00106 0.00107 0.00108 0.00108 0.00109 Sum of Squares of Residuals 2.958E-04 2.951E-04 2.953E-04 2.958E-04 2.964E-04 Corrected determination coefficient 0.99807 0.99807 0.99807 0.99807 0.99807 Impurity content / % 0.180 0.182 0.184 0.185 0.186 Indomethacin purity / % 99.820 99.818 99.816 99.815 99.814 <![CDATA[S m / m]]> 0.0156 0.0156 0.0156 0.0155 0.0156 <![CDATA[Uncertainty 2×S m / m (k = 2)]]> 0.031 0.031 0.031 0.031 0.031

[0074] The number of points is 9; the degrees of freedom are 7.

[0075] The literature does not provide the purity of the principal component comparison method, and given that the units of purity measurement are different (mol% and m%), the empirical formula takes D... 2 R =0.102A 总 The traditional method uses Δ = 0.102A. 总 The parameters (correction coefficient of determination and residual sum of squares) of the two fitted lines are the same, and the calculated purity values ​​differ by 0.017%. The calculation results of the two methods are in agreement (the units of measurement may be the same or different).

[0076] In this embodiment, the purity of the principal component is greater than 99.8%, and the correction factor Δ in the traditional method is ridiculously high, reaching 30 times 10.2%.

[0077] If the traditional method uses the same Δ value to correct ΔH F The impurity content will increase proportionally. In this example, the corrected impurity content is 0.18 mol%, and the indomethacin purity is 99.82 mol%, which aligns with the empirical formula (P... i =P 2 i The calculation results may match, and the units of measurement may be the same or different.

[0078] Example 2: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0079] This embodiment compares the results of traditional methods with those calculated using literature (Chen Qing, Wei Borong, Bao Dejun. Differential scanning calorimetry for single-peak determination of substance purity, Analytical Instruments, 2005, (3): 42-46) and empirical formulas.

[0080] Instruments: Differential scanning calorimeter and analysis software from Perkin Elmer.

[0081] The document argues that "T" s The 1 / F curve is not a straight line. The main reason is that when the experimental process has reached thermal equilibrium, the sample has not yet formed an ideal solid solution, but the DSC experimental curve has already begun recording (this phenomenon is called "pre-melting" of the sample), leading to a lower fraction F of the initial melt obtained from the DSC curve. Pre-melting affects the temperature range from the start of melting to the highest point of the melting peak. The heat required for pre-melting is approximately between 0% and 20% of the total enthalpy of fusion, therefore a correction is needed to compensate for the lost heat.

[0082] Table 4 lists the partial melting area and 1 / F data from the literature (the literature does not distinguish between F and F').

[0083] Table 4. Partial melting area and 1 / F data from the literature.

[0084]

[0085] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔH F ) / P i (1) Calculation;

[0086] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0087] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0088] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0089] m is the content fraction of impurities in the sample;

[0090] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0091] P i (P 1 i and P 2 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample).1 R and D 2 R The area fraction of ). P i According to formula (P) i =P 2 i D 2 R =0.152A 总 The calculated results are consistent with the values ​​of impurity and main component purity obtained by traditional methods; however, the units of measurement may be the same or different. Table 5 shows a comparison between the calculation results of this embodiment and the calculation results of traditional methods.

[0092] Table 5. Comparison of calculation results from this embodiment and traditional methods

[0093]

[0094] In this embodiment, the purity of the main component is greater than 99.5%, A 总 The correction percentage reached an absurdly high 15%, which cannot be explained by pre-melting phenomena. The empirical formula (P...) i =P 2 i The results are in good agreement with the traditional methods of enthalpy correction without 15% and enthalpy correction, with differences of 0.07% and 0.012%, respectively.

[0095] The authors of the literature confirmed that the measurements and calculations were performed under the following conditions: (1) according to the Van't Hoff formula; (2) the presence of pre-melting; and (3) Δ = 0.15A. 总 (4) The purity of the main component is 99.55 mol%.

[0096] Based on this, we can draw the following conclusions: (1) Because the compensation area △ / A 总 It should be roughly equivalent to twice the impurity mol fraction. Therefore, the data in this embodiment is ridiculously high (17 times), and the above points (2) to (4) are incompatible with each other; (2) The differential scanning calorimeter and analysis software of Perkin Elmer do not show the above incompatible contradictions, indicating that the random analysis software has room for further intelligentization.

[0097] Regarding the effectiveness of the linear fitting model: the closer the correction coefficient of determination is to 1 and the smaller the sum of squared residuals, the better the linear fitting model. The formula provided in this embodiment (P) i =P 2 i The two parameters of the fitted line are better than those of the traditional method.

[0098] Example 3: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0099] This embodiment compares the results calculated using the traditional method from the literature (Wang Fang, Tu Qiang, Li Yi, et al. Determination of purity of milrinone by differential scanning calorimetry, Chemical World, 2012, 53(6): 338-341) with the results calculated using the formula provided in this embodiment.

[0100] Instrument: PE Diamond differential scanning calorimeter (Perkin Elmer, USA).

[0101] The data for each point in this document are shown in Table 6.

[0102] Table 6. Calculated values ​​of data points at various points on the Milrinone DSC peak

[0103] 1 2 3 4 5 6 7 8 9 10 T / K 588.05 588.15 588.25 588.35 588.40 588.45 588.50 588.55 588.60 588.65 Percent / % 2.23 4.86 8.82 14.44 18.02 22.22 27.22 33.21 40.29 48.18 1 / F 44.84 20.58 11.34 6.93 5.55 4.50 3.67 3.01 2.48 2.08

[0104] The literature does not provide the value of the correction factor Δ. Using a trial-and-error method, given the slope of the fitted line = 0.06762 and the intercept = 588.72K, the value of Δ = 0.08A can be obtained. 总 The intercept of the fitted line is 588.718K, SD 截距 =0.02514; slope = -0.06762, SD 斜率 =0.00458; Sum of squared residuals = 1.23E-2; Correction coefficient of determination = 0.96018; Comparison of Milrinon literature data curve (B) and fitted line (Linear Fit of B) Figure 1 (1 / F'-T)(△=0.08A 总 (Calculated using Origin software) See Figure 1 ; Use 1 / P to plot the graph using precise formula data. 2 ).

[0105] from Figure 1 The graph shows a correction factor Δ = 0.08A. 总 Not a suitable match.

[0106] Comparison chart of data curve (B) and fitted line (Linear Fit of B) in Table 7 of Milrinon (P) 2 ;D 2 R =0.242A 总 (Calculated using Origin software) See Figure 2 .

[0107] Table 7 shows the purity and impurity content of milrinone, the calculation results of this embodiment and the calculation results of the traditional method.

[0108] Table 7 shows the milrinone purity and impurity content calculated using this embodiment and the traditional method.

[0109]

[0110]

[0111] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔH F ) / P i (1) Calculation;

[0112] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0113] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0114] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0115] m is the content fraction of impurities in the sample;

[0116] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0117] P i (P 1 i and P 2 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample). 1 R and D 2 R The area fraction of ). P i According to the empirical formula (P) i =P 1 i D 1 R =△) and (P i =P 2 i D 2 R =0.242A 总 The calculated values ​​for impurity and main component purity are in good agreement, but the units may be the same or different; by selecting a fitted linear formula under specified conditions, a better fitted linear formula than reported in the literature can be obtained (compare Δ = 0.08A).总 In this embodiment, the optimized value of Δ is: Δ = 0.242A. 总 and D 2 R =0.242A 总 ).

[0118] Example 4: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0119] This embodiment provides the determination of the purity of 2-fluoro-3-chlorobenzenesulfonamide.

[0120] Instrument: PE Corporation DCS 8500 (2010)

[0121] Sample weight: 1.080 mg. The DSC curve provides the following parameters:

[0122] Limit1=154.66℃(6.19%); Limit2=155.18℃(60.36%); △H F =39.87 kJ / mol; T m =154.90℃; T o =154.92±6.30E-3℃; △=1.21±0.39%A 总 Method: Standard; X1 = 153.08℃; X2 = 156.68℃; Mol. Wt. = 209.63 g / mol; Heating rate: 0.50℃ / min. Purity = 99.94 ± 0.01% (Impurities = 0.06 ± 0.01 mol%).

[0123] The purity determination curve and parameters of 2-fluoro-3-chlorobenzenesulfonamide (calculated using PE randomization software) are shown below. Figure 3 The fitted line of its 1 / F' is shown in [reference needed]. Figure 4 The comparison chart of the line connecting the data in the interval of 1 / F' values ​​1-19 in Table 8 of this invention (B) and the fitted straight line (Linear Fit of B) (1 / F'-T; Δ = 0.0121A) is shown. 总 (Calculated using Origin software) See Figure 5 The comparison chart of the line connecting the data in the interval of 1 / F' values ​​2-18 in Table 8 calculated by this invention (1 / F'-T; Δ=0.0121A) is shown. 总 (Calculated using Origin software) See Figure 6 The range of values ​​for 1 / F' calculated in this embodiment is (Δ = 0.0121A). 总 See Table 8.

[0124] Table 8. Data on the range of values ​​for 1 / F' in this embodiment.

[0125]

[0126] Table 9.1 Effects of different ranges of / F' values ​​(△=0.0121A) 总 )

[0127] serial number 1 2 3 4 5 Data range 1-19 2-17 2-18 3-17 3-18 Intercept / K 154.908 154.898 154.8976 154.897 154.896 <![CDATA[SD 截距 / K]]> 0.00601 0.00159 0.00152 0.00175 0.00164 slope -0.01851 -0.01772 -0.01765 -0.01761 -0.01754 <![CDATA[SD 斜率 ]]> 6.611E-4 1.87E-04 1.70E-4 2.00E-04 1.79E-04 Points 19 16 17 15 16 Degrees of freedom 17 14 15 13 14 Sum of Squares of Residuals 2.27E-03 8.97E-05 9.57E-05 7.89E-05 8.29E-05 Corrected determination coefficient 0.97754 0.99833 0.99852 0.99819 0.99844 Impurities / mol% 0.0484 0.0464 0.0462 0.04614 0.0459 Main component purity / mol% 99.952 99.954 99.954 99.954 99.954 <![CDATA[S x / X]]> 0.036 0.011 0.010 0.011 0.010 <![CDATA[Uncertainty 2×S x / X(k = 2)]]> 0.071 0.021 0.019 0.023 0.020

[0128] from Figure 5 , Figure 6 As shown in Table 9, after removing outliers at both ends, the fitted straight line for the data interval with the largest corrected coefficient of determination (2-18) is obtained (see Table 9). Although taking data points 3-17 yields a smaller sum of squared residuals, it also results in a smaller corrected coefficient of determination. In this case, the data with the largest corrected coefficient of determination among the data points is preferred. Based on the data in this interval (2-18), the impurity content is calculated to be 0.0462 mol%, and the purity of 2-fluoro-3-chlorobenzenesulfonamide is 99.954%. Although the impurity content and principal component purity differ in other intervals, the differences are not significant.

[0129] The SD of the slope in interval 2-18 is more than 3 times smaller than the SD of the slope in interval 1-19; this will reduce the calculated SD of impurity content and principal component purity.

[0130] The optimal Δ values ​​for the data range of 2-18 in Table 9 are shown in Table 10.

[0131] Table 10. Optimal Δ values ​​for the data range 2-18

[0132] serial number 1 2 3 4 5 △ <![CDATA[0.0135A 总 ]]> <![CDATA[0.0134A 总 ]]> <![CDATA[0.0133A 总 ]]> <![CDATA[0.0132A 总 ]]> <![CDATA[0.0130A 总 ]]> Intercept / K 154.8989 154.8988 154.8987 154.8986 154.8984 <![CDATA[SD 截距 / K]]> 0.00152 0.00152 0.00152 0.00151 0.00151 slope -0.01802 -0.018 -0.01797 -0.01794 -0.01789 <![CDATA[SD 斜率 ]]> 1.72E-04 1.72E-04 1.72E-04 1.72E-04 1.71E-04 Points 17 17 17 17 17 Degrees of freedom 15 15 15 15 15 Sum of Squares of Residuals 9.444E-05 9.443E-05 9.442E-05 9.443E-05 9.450E-05 Corrected determination coefficient 0.99854 0.99854 0.99854 0.99854 0.99854 Impurities / mol% 0.0472 0.0471 0.0470 0.0470 0.0468 Main component purity / mol% 99.953 99.953 99.953 99.953 99.953 <![CDATA[S x / X]]> 0.00956 0.00956 0.00956 0.00956 0.00956 <![CDATA[Uncertainty 2×S x / X (k = 2)]]> 0.019 0.019 0.019 0.019 0.019

[0133] In the formula of this embodiment, according to formula (P) i =P 1 i D 1 R =△) The results obtained by calculation are consistent with the values ​​of impurity and main component purity obtained by traditional method (Table 10), but the units of measurement are different.

[0134] This embodiment follows the empirical formula (P) i =P 2 i D 2 R The calculated results are listed in Table 11.

[0135] Table 11. Empirical Formulas (P) i =P 2 i D 2 R The result of the calculation

[0136] serial number 1 2 3 4 5 <![CDATA[D 2 R / A 总 / %]]> 1.35 1.33 1.32 1.31 1.30 Intercept / K 154.899 154.899 154.899 154.899 154.898 <![CDATA[SD 截距 / K]]> 0.00152 0.00152 0.00151 0.00151 0.00151 slope -0.01827 -0.01821 -0.01818 -0.01815 -0.01812 <![CDATA[SD 斜率 ]]> 1.746E-04 1.741E-04 1.738E-04 1.735E-04 1.733E-04 Points 17 17 17 17 17 Degrees of freedom 15 15 15 15 15 Sum of Squares of Residuals 9.444E-05 9.442E-05 9.443E-05 9.446E-05 9.4496E-05 Corrected determination coefficient 0.99854 0.99854 0.99854 0.99854 0.99854 Impurities / % 0.0478 0.0477 0.0476 0.0475 0.0474 Main component purity / % 99.952 99.952 99.952 99.952 99.953 <![CDATA[S m / m]]> 9.6E-03 9.6E-03 9.6E-03 9.6E-03 9.6E-03 <![CDATA[Uncertainty 2×S m / m (k = 2)]]> 1.9E-02 1.9E-02 1.9E-02 1.9E-02 1.9E-02

[0137] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔH F ) / P i (1) Calculation;

[0138] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0139] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0140] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0141] m is the content fraction of impurities in the sample;

[0142] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0143] P i (P 1 i and P 2 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample). 1 R and D 2 R The area fraction of ). P i According to formula (P) i =P 2 i D 2 R )D R =0.0133A 总 The correction determination coefficient and residual sum of squares are the same as those of the traditional method; the two methods agree on the results of calculating the purity of impurities and main components (but the units of measurement are different); the sample in this embodiment was measured to be 99.97% by the normalization method of light absorption area at a wavelength of 254 nm by HPLC, and the calculation results of the formula provided in this embodiment agree with the comparison method.

[0144] Example 5: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0145] Sample: 2-fluoro-3-chlorobenzenesulfonamide; Heating rate: 1.00℃ / min; Sample weight: 7.350 mg; A i Interval: (1.000%~10.002%)A 总 Temperature range: 147.52~153.31℃; △ / A 总 =3.89%.

[0146] This embodiment aims to compare the influence of the 1 / F' value range. The determination curve and parameters of the purity of 2-fluoro-3-chlorobenzenesulfonamide (calculated using PE randomization software) are shown below. Figure 7 The fitted straight line of 1 / F'-T (calculated using PE stochastic software) is shown below. Figure 8 Based on the comparison chart (1 / F'-T) of the data line (B) and the fitted straight line (Linear Fit of B) in Table 12 (calculated using Origin software), see [link to Origin software]. Figure 9 .

[0147] The Influence of the Value Range of Traditional Method 1 / F' and its Comparison with Empirical Formula (A) i = (1% ~ 10%)A 总 See Table 12.

[0148] Table 12. The Influence of the Value Range of 1 / F' in the Traditional Method and a Comparison with the Formula in This Embodiment (A) i = (1% ~ 10%)A 总 )

[0149]

[0150] Figure 9 The display shows that the data line and the fitted straight line of input data number 1 (sampling points 1741) in the PE random software deviate significantly at both ends. After deleting the data with significant deviations at both ends, the fitted straight line of input data number 4 (sampling points 883) has the maximum value of the correction determination coefficient and the minimum value of the residual sum of squares. Although there is no significant difference in impurity content, the SD of the intercept and slope is significantly smaller than that of data number 1.

[0151] The formula (P) in this embodiment i =P 2 i D 2 R )D 2 R =0.0133A 总 The correction determination coefficient and residual sum of squares are the same as those of the traditional method; the calculated values ​​of impurity and principal component purity by the two methods are in agreement (although the units of measurement are different).

[0152] If △H F Also according to A 总The correction percentage value is corrected, and the impurity content of No. 4 is 0.783 / mol%, indicating the purity of the main component.

[0153] = 99.217 mol%. Whether or not correction is applied has a negligible impact on the result.

[0154] In A i = (1-10%)A 总 Interval, traditional method (uncorrected or corrected ΔH) F The calculation results of the formula provided by this invention are consistent (the units of measurement are different).

[0155] Example 6: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0156] This embodiment aims to provide a method when △ / A 总 The calculation method when the value is negative.

[0157] Sample: 2-fluoro-3-chlorobenzenesulfonamide; heating rate: 1.00℃ / min; sample weight: 7.350mg.

[0158] The purity determination curve and parameters of 2-fluoro-3-chlorobenzenesulfonamide (calculated using PE random software) are shown below. Figure 10 .

[0159] The fitted straight line of 1 / F'-T (calculated using PE stochastic software) is shown below. Figure 11 .

[0160] from Figure 10 It can be seen that X-Corrtn(△ / A) 总 = -0.67%.

[0161] Figure 11 It can be seen that X-Corrtn(△ / A) 总 The linearity of the fitted line is -0.67%, indicating good linearity.

[0162] Optimize △ / A 总 The range of 1 / F' values ​​from -0.67% to -0.73% is shown in Table 13.

[0163] Table 13 shows the optimized △ / A. 总 = -0.67% to -0.73% 1 / F' value range. Temperature range: 153.27~154.31℃. A i Interval: (10.5242%~29.1722%)A 总 .

[0164] Table 13. Optimization of △ / A 总 =Data within the range of 1 / F' from -0.67% to -0.73%

[0165]

[0166] Optimize D 2 R / A 总 = -0.70% to -0.73% of 1 / P 2 The data range is shown in Table 14.

[0167] Table 14. Optimization D 2 R / A 总 = -0.70% to -0.73% of 1 / P 2 Value range data

[0168]

[0169]

[0170] Temperature range: 153.27-154.31℃. A i Interval: (10.5242% - 29.1722%)A 总 .

[0171] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔH F ) / P i (1) Calculation;

[0172] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0173] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0174] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0175] m is the content fraction of impurities in the sample;

[0176] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0177] P i (P 1 i and P 2 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample).1 R and D 2 R (Fraction of the melting endothermic peak area after ) P i In this embodiment, P is taken as i 1 When formulating the scheme, the total melting enthalpy redistribution parameter D of the sample 1 R The value can be negative.

[0178] Because in traditional methods, it is believed that during the determination of the above samples, due to "instrument insensitivity, early melting" cannot be detected, the compensation area △ / A 总 The requirement to take a positive value leads to a significant deviation in the calculation results; however, in this embodiment, △ / A is used. 总 By taking a negative value, we can fully consider the thermal hysteresis caused by the kinetics, which leads to the coexistence of two phases, namely, a solid phase S dissolving into a liquid phase L (SL) during the process from the start of melting to full melting, and the redistribution of the overlapping thermal effects of the previous continuous "seamless" connection, thus obtaining more accurate calculation results.

[0179] The determination curve and parameters for the purity of 2-fluoro-3-chlorobenzenesulfonamide were calculated using PE randomization software (see...). Figure 10 The fitted straight line of 1 / F'-T (calculated using PE random software) is shown below. Figure 11 )△ / A 总 = -0.67 ± 0.08%; Optimized △ / A 总 The value is -0.72% (see Table 13). Although the optimized value still falls within the range given by the PE random software, the center value deviates from 0.05.

[0180] In this example, we take P. 1 i When considering the plan, when D 1 R When the Δ is the same as that of the traditional method, the values ​​of impurity content and main component purity obtained by the two methods are consistent (although the units of measurement are different).

[0181] In the formula provided in this embodiment, the formula (P) is taken. i =P 2 i D 2 R )D 2 R = (-0.0071-0.0072)A 总 A 总 The correction determination coefficient and residual sum of squares are the same as those of the traditional method; the two methods are in agreement on the calculation results of impurity and principal component purity (different units of measurement) (see Tables 13 and 14).

[0182] Examples 5 and 6 use the same sample, the same heating rate, but with different A values. i The data range; although the correction determination coefficient of Example 5 is slightly higher than that of Example 6 (0.99995 slightly greater than 0.99991), the residual sum of squares of Example 5 is much greater than that of Example 6 (0.0317 much greater than 0.00025); at the same time, the purity of 99.71% measured in Example 6 is consistent with the HPLC value of 99.81% measured by the comparative method (254nm light absorption area normalization method), while the purity of 99.19% measured in Example 5 is far different from the HPLC value of 254nm light absorption area normalization method.

[0183] Therefore, it can be proven that in the formula provided by this invention, when △ / A 总 When the value is negative, it should be determined according to the formula (P). i =P 2 i D 2 R This method overcomes the shortcomings of traditional methods where compensation is negative and accurate calculation results cannot be obtained. It also proves that the calculation method provided by this invention overturns the conclusion that such substances cannot be accurately calculated due to problems such as instrument insensitivity.

[0184] Example 7: A method for calculating the purity of organic crystalline substances using DSC single-peak method

[0185] When using: P 1 i =(A i +D 1 R ) / (A 总 +D 1 R When ), the formula and the traditional method both use F=(A) i +△) / (A 总 +△) are similar in form, but have different physical meanings; in D 1 R Under the condition that the value of is equal to △, the empirical formula can obtain the same values ​​of impurity content and main component purity calculated by traditional methods, but the units can be the same or different.

[0186] This embodiment lists some data from the literature and presents comparative examples that use the formulas provided by this invention and the comparison method, but use different units of measurement than the traditional method (data with a purity >100% and indeterminate values ​​are excluded). Detailed data are shown in Table 15.

[0187] The formula provided in this embodiment uses T. i =T0-(RT0) 2 m / ΔHF ) / P i (1) Calculation;

[0188] Among them, T i Is the sample at t i Temperature at any given moment, measured in Kelvin (K).

[0189] T0 is the melting point of the pure principal component obtained by extrapolation from the fitted linear equation, and the unit is K;

[0190] R is the ideal gas constant (8.314 J·mol⁻¹). -1 ·K -1 );

[0191] m is the content fraction of impurities in the sample;

[0192] △H F It is the enthalpy of fusion of the main component (J·mol⁻¹) -1 ), and set the melting enthalpy of the impurities and the melting enthalpy of the main components to be equal, and both to be constants that do not change with temperature;

[0193] P i (P 1 i ) is the redistribution parameter (D) introduced from the DSC melting endothermic peak area (enthalpy of fusion of the sample). 1 R The area fraction of the melting endothermic peak after melting). Depending on the sample composition and melting process, P i The formula for calculating P is: 1 i =(A i +D 1 R ) / (A 总 +D 1 R ), 1 / P 1 i =(A 总 +D 1 R ) / (A i +D 1 R ); where A i From the point where the DSC curve deviates from the baseline to t i The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 1 R It is the redistribution parameter of the enthalpy of melting of the sample, that is, the redistribution parameter of the area of ​​the overlapping endothermic melting peaks before the process of solid phase S dissolving into liquid phase L (SL) during the process of the sample from the beginning of melting to complete melting; or P2 i =(A i +D 2 R ) / A 总 , 1 / P 2 i =A 总 / (A i +D 2 R A i From the point where the DSC curve deviates from the baseline to t i The area under the curve at time intervals; A 总 It is the total area under the curve of the sample from the start of melting to complete melting; D 2 R It is the redistribution parameter of the enthalpy of melting of the sample, that is, the redistribution parameter of the area of ​​the overlapping melting endothermic peak before the process of solid phase S dissolving into liquid phase L (SL) coexisting during the process of the sample starting to melt and going to full melt.

[0194] Table 15. Comparison of principal component purity using traditional methods, the method of this invention, and comparative methods in the literature.

[0195]

[0196]

[0197]

[0198]

[0199] Table 15 uses the mass balance method as a comparison method. Kang Ma (2009; sample water content 0.11%; impurity 1: 0.019%; impurity 2: 0.049%), Xu Peng (2013; sample contains organic impurities: 0.12%; water: 0.02% and ash: 0.01%), and Zhou Jinyan (2018; sample contains 4 impurities; water: 0.062% and ash: 0.060%). From the above data, it can be determined that the samples in the above literature belong to ternary or more elemental systems.

[0200] In the calculation method provided by this invention, when SD is known... △H Given the same data, the uncertainty of impurity content and purity can be easily obtained by using the error propagation formula.

[0201] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been shown above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for calculating the purity of an organic crystalline substance by DSC unimodal method, characterized in that, The purity of the organic crystalline substance is calculated using the following formula: ; wherein, T i is the temperature of the sample at time t i in K; T 0 Tm is the melting point of the pure principal component obtained by linear extrapolation, in K; R is the ideal gas constant, 8.314 J-mol -1 ·K -1 ; m is the fraction of the sample that is impure; is the melting enthalpy of the main component in J-mol -1 and the melting enthalpy of the impurity is set to be equal to the melting enthalpy of the main component and is a constant that does not change with temperature; P i It is the result of introducing the redistribution parameter in t i The fraction of the melting absorption peak area of ​​the sample at time point; the P i The formula for calculating P is: i =(A i +D 2 R ) / A 总 The value of Pi is limited to a process range in which solid phase S dissolves in liquid phase L, and the two phases coexist. wherein A i is the area of the interval from the beginning of the deviation of the DSC curve from the baseline to the time instant t i ; A 总 is the total area of the envelope under the curve from the beginning of the melting of the sample to the end of the melting process; D 2 R is the redistribution parameter of the melting enthalpy of the sample, i.e. the area of the envelope under the DSC curve A 总 is the redistribution parameter of the area of the melting endotherm peak in the process of the coexistence of the solid phase S and the liquid phase L from the beginning of the melting of the sample to the end of the melting process and before this process, taken in a certain temperature interval and in different temperature intervals, the values of D 2 R corresponding to the formula (1) have the least value of the sum of the squares of the residuals under the condition that the coefficient of determination is closest to 1.

2. The method of claim 1, wherein the method is characterized by: The content fraction of the impurities in the sample is mass fraction, mol fraction or light absorption area fraction at a specified wavelength.

3. The method of claim 1, wherein the method is a DSC unimodal method for determining purity of an organic crystalline substance. The D 2 R Values are from DSC curves of A i -T i selected from the data column of T onset -T peak partial data pairs in the data column.

4. The method of claim 3, wherein the method is characterized by: The T onset - T peak The data pair in the data column is greater than or equal to 8 pairs.

5. The method of claim 1, wherein the method is a DSC unimodal method for determining purity of an organic crystalline substance. The method is used for calculating the sample with the total content of impurities of organic crystalline substance ≤3% and the purity of main component ≥97%.

6. The method of calculating the purity of an organic crystalline substance by DSC single peak method according to claim 1, characterized in that, The method is used for calculating the sample with the total content of impurities of organic crystalline substance ≤2% and the purity of main component ≥98%.

7. The method of claim 1, wherein the method is a DSC unimodal method for determining purity of an organic crystalline substance. The formula (1) is used for the intermediate control and the initial inspection of products in the production of synthetic materials.

8. The method of calculating the purity of an organic crystalline substance by DSC single peak method according to claim 1, characterized in that, The formula (1) is used for calculating the purity of organic crystalline substance of the sample not conforming to the binary simple eutectic condensation system.

9. The method of claim 1, wherein the method is a DSC unimodal method for determining purity of an organic crystalline substance. The formula (1) is used for calculating the purity of organic crystalline substance of the sample not conforming to the binary simple eutectic condensation system.

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