在药物生产制造过程中，片剂体积、密度和孔隙率是相互关联的参数，并且对于控制药物的生产质量非常重要。为了实现药物的有效封装以及良好的患者接受度，药物片剂需要具有一致的尺寸和形状。
由于包裹密度可能会受到不同压实程度的影响，因而包裹密度是评估片剂一致性的有效参数。而通过控制颗粒混合物的骨架密度，可以使其在压片过程中达到适宜的流动性和可压缩性。
孔隙率会影响溶剂渗透片剂固体基质的难易程度，因此通常作为片剂（或颗粒产品）的关键质量属性（CQA）。溶剂渗透速率会影响片剂的崩解和溶出过程，并进一步影响药物的生物利用度和临床疗效。因此，如果两种片剂所含的活性药物成分（API）质量相同，但两者孔隙率不同，那么高孔隙率的片剂会更快地溶解，进而更快地释放 API。尽管在不同批次中片剂间的孔隙率变化是不可接受的，但可以根据不同的临床需求对孔隙率进行调整，以实现不同的溶出速率。因而，需要快速溶出的片剂通常具有较高的孔隙率。这些相关参数将在下文的 “物理特性入门” 中介绍。

麦克仪器的 AccuPyc 系列气体置换法密度仪和 GeoPyc 系列包裹密度分析仪分别可以测量材料的骨架体积和包裹体积，结合质量可由此算得相应的密度值。同时，这两款仪器都可以根据另一台所提供的密度生成相应的孔隙率值。

这些功能使得这两种仪器成为制药应用中，尤其是在片剂和料带的分析中很有价值的组合。本文介绍了由这两款仪器单独或组合使用获得的一系列药物片剂测试结果。

仪器介绍

AccuPyc 气体置换法密度仪

The AccuPyc is a gas pycnometer, it works by having two chambers, a sample chamber, and an expansion chamber, both with carefully calibrated volumes. A sample is loaded into the sample chamber and pressurized through valve a, the equilibrated pressure is then recorded using the transducer t. The gas is then expanded through valve b to the expansion chamber where the equilibrated pressure is again recorded. Using the ideal gas law, the volume occupied by the sample can be calculated from the known volume of the chambers and measured pressure values. The volume measured is the skeletal volume of the sample, since gas penetrates all accessible pore space. A more complete description of this is available in our application note 180 “Measuring the volume, density and porosity of tablets for coating process control and QC”.

The AccuPyc measures skeletal volume by gas pycnometry

The GeoPyc Envelope Density Analyzer

The GeoPyc uses a precision cylinder of known diameter which is filled with a free-flowing quasi-fluid solid displacement media to enable measurement of envelope volume.

The cell is oscillated, to vibrate the media, which is simultaneously compressed to a defined consolidation force to establish the media volume (position A, in the Step 1: Blank). The sample is then added into the cylinder and the compaction process is repeated (position B, in the Step 2: Measurement).

The volume of the sample is calculated from the difference in the distance that the piston travels to achieve an equivalent consolidation force (h, the distance between positions A and B, in the Step 2: Measurement box).

The Micromeritics® DryFlow displacement media conforms to the surface of the sample during measurement but does not penetrate any pore space. The media forms a tightly compacted layer around the sample regardless of the sample’s geometry. The resulting volume is therefore described as the envelope volume.

The GeoPyc measures envelope volume by solid phase displacement

Experimental Details

Samples of indigestion and enterically coated Aspirin tablets were tested using the AccuPyc and GeoPyc. The indigestion tablets are uncoated, designed to be chewed in the mouth and swallowed. They react and dissolve in the acid of the stomach. In contrast, the Aspirin tablets are polymer coated to allow them to pass through the stomach intact. While the polymer does not react with the acid of the stomach, it rapidly breaks down in the more alkaline conditions of the small intestine, allowing targeted dissolution and API absorption.

The tablets were tested whole, scratched (to simulate damage to the coating) and halved. Thus, testing the ability of the systems to detect defects in the coating layer. Both types of tablets were treated in the same way to generate a comprehensive set of comparative data; where the uncoated tablets act as a control, and duplicate tests were performed for each sample.

All sample preparation and testing, including system calibrations, data collection for 12 sample sets and bookend tests was completed in around 4.5 hours.

Full details of the experimental methods, instrument settings used, and data processing steps applied can be found in separate white paper. Please contact us for additional information on the white paper.

Results and Data Analysis

Difference plots for the two sets of tablets, showing skeletal density and porosity are given below. These two parameters exhibited the most change, from sample to sample. The difference values were produced by subtracting the lowest value of each dataset, the value for the whole tablet in each case, from each of the other values.

Looking first at the data for the change in skeletal density (left graph), it is clear that scratching or halving has a much greater impact on the coated Aspirin tablet (turquoise bars) than the uncoated indigestion tablet (green). With the indigestion tablet, the response is roughly double for halved as compared to scratched, but in absolute terms the change observed is approximately comparable to the error associated with the measurements. The statistical significance of this trend is, therefore, weak. In contrast, scratching of the Aspirin results in a significant change in density, with further damage (halving) only giving rise to a modest further change. These results suggest that change in skeletal density may be a sensitive indicator of damage to the tablet coating.

The porosity data for the coated Aspirin (right graph – purple bars) shows a more linear trend, from whole to scratched to halved, is seen. This may also be sufficiently sensitive to detect coating damage. These data suggest that the tablet becomes more porous, once the interior, uncoated material is exposed, an expected result. The results for the indigestion tablet (blue bars) shows a more marked trend than expected, particularly given the density data. They suggest that the tablet is not homogeneous, but rather that the outer surfaces of the tablet are denser and less porous than the center, possibly as a result of non-uniform compaction in the tablet press. Taken together, the two sets of data indicate that while porosity could be used to detect an issue with coating integrity, it is a less useful parameter than density, since both coated and uncoated tablets show the same trend.

Difference plots of density or porosity change for both tablet types versus damage to tablet. Showing the impact of scratching and halving is more marked for the coated Aspirin tablets

Conclusion

This study highlights the value of the AccuPyc and GeoPyc to be used in combination for the fast and simple monitoring of the coating integrity of tablets for process control or in QC.

Together the AccuPyc and GeoPyc enable the rapid and reliable measurement of five physical characteristics, all of which may be exploited for pharmaceutical process control.

The data presented here clearly show that:

• Both porosity and skeletal density change as a result of loss of integrity of a tablet coating
• The density results are sufficiently discriminating to detect even relatively minor surface defects

Physical Properties Primer – Density, Volume and Porosity

密度

At first sight, density is a relatively straight forward term defined as mass divided by volume. On a lab scale, values are typically stated in g/cm³ . However, there are multiple ways to define and quantify volume. Each gives rise to a different density parameter.

Volume

In the study described here, envelope and skeletal density were determined from measurements of:

• Envelope volume, which is the volume the sample occupies in space, including both the solid content of the sample and any pore space or voids within it
• Skeletal volume, which is the volume of actual solid that makes up the sample

孔隙率

Porosity is a dimensionless value, normally quoted as a percentage. It quantifies how much of a sample is solid and how much is empty space. Porosity can be calculated using the equation below when working with volume values and is independent of mass. There is also a corresponding equation that can be used with density values, as porosity is independent of mass the volume equation is preferred here.

The solid fraction can also be calculated from a knowledge of porosity and is given by the equation:

These values are interrelated where porosity describes the amount of empty space and solid fraction describes the amount of solid in any given sample. Therefore, a high value for solid fraction indicates a high solid content in the sample, and this would correspond to a low porosity. Conversely, a high value for porosity indicates a high total pore volume in the sample, and would correspond to a low solid fraction value.