A Fast and Non-destructive Terahertz Dissolution Assay for Immediate Release Tablets

THz porosity correlated linearly with nominal porosity for biconvex tablets even though the APIs absorb THz radiation relatively strongly.

“Despite the use of relatively high terahertz absorbing APIs, Fig. 3 shows excellent linear correlations between the measured terahertz porosity, fTHz, and the nominal porosity, fnominal.”

Debossing had a negligible effect on the THz porosity measured from tablets.

“In other words, the presence of debossing, as typically found on most commercial tablets, has negligible impact on the measured terahertz porosity.”

• AssumptionRests on an assumption: Debossing is common on commercial tablets.

Using placebo biconvex tablets with comparable excipients, tablet porosity was measured accurately when the THz acquisition time was cut to roughly 0.12 s.

“In this study using a given placebo biconvex tablets with a similar excipient composition as the current formulations, we have shown that it is possible to accurately measure the porosity of tablets by reducing the acquisition time to about one eighth of a second (0.12 s).”

For flat-faced tablets, placebo tablets, and non-debossed biconvex tablets, the terahertz porosity values correlated strongly with the nominal porosity values.

“To further buttress the robustness of the terahertz porosity measurement method, excellent correlations between fTHz and fnominal were obtained for the flat-faced tablets (see Fig. S4 in the supplementary information), the placebo tablets (Fig. S2 in the supplementary information) and the non-debossed biconvex tablets (Table 3 and in Fig. S6 in the supplementary information).”

Apart from scattering in the indomethacin tablet data, dissolution time and measured terahertz porosity showed a generally good correlation.

“Aside from the seemingly 15 scattering in the data of the indomethacin tablets (Fig. 5 (b) & (c)), a generally good correlation 16 can be observed between dissolution time and the measured terahertz porosity.”

Terahertz porosity and nominal porosity showed an excellent linear correlation.

“The excellent linear correlation observed between the terahertz porosity and the nominal porosity has manifested the robustness of the terahertz approach for tablet porosity measurement even for tablets containing high absorbing APIs, embossing and of different geometries.”

• Also stated in: § 4. Conclusions · plain

  “The excellent linear correlation between the measured terahertz porosity, fTHz, and the 2 nominal porosity, fnominal.”

A similar gel-related phenomenon was observed in this study.

“A similar phenomenon is observed in this study (see Fig. 5(d)), which explains our choice to use a polynomial regression method.”

The current samples showed an excellent correlation between tensile strength and terahertz-based porosity.

“Despite our previous study that has revealed that hardness does not always correlate with the porosity (especially for granulated samples) 17 , the current samples have shown excellent correlation between the tensile strength and terahertz-based porosity values (Fig. 6).”

Ibuprofen appeared to dissolve faster from the tablets than indomethacin.

“Although 17 ibuprofen appears to dissolve faster from the tablets than indomethacin, porosity is again and 18 unsurprisingly seen to play a major role in the tablet dissolution kinetics.”

For all tablet sets, second-order polynomial fitting of disintegration versus terahertz porosity gave averaged R-squared of about 0.99 and RMSE of about 0.2 min.

“Second order 8 polynomial data fitting was performed and the averaged fitting parameters that were obtained 9 for all sets tablet were R 2 ≈ 0.99 and RMSE ≈ 0.2 min.10”

For F1-Ibup and F2-Ibup flat-faced tablets, effective refractive index and nominal porosity showed an excellent linear correlation, with R-squared of 0.999 and RMSE of 0.0024 for F1-Ibup and R-squared of 0.999 and RMSE of 0.0017 for F2-Ibup.

“(b) and (c) show an excellent linear correlation between the effective 4 refractive index and the nominal porosity with a coefficient of correlation of R 2 = 0.999, root 5 mean square error of RMSE = 0.0024 and R 2 = 0.999, RMSE = 0.0017 for the F1-Ibup and F2-6”

The placebo tablet results show that the acquisition time can be reduced to one eighth of a second.

“Adding to the above merits, the results obtained from the placebo tablets (Fig. S2 in the supplementary information) have proven the possibility of even scaling the acquisition time down to one eighth of a second.”

Using THz-TDS, the porosity of different tablet types was measured directly and quickly, within 1 s.

“By using THz-TDS, the porosity of different kinds of tablets was directly measured in a fast manner (≤ 1 s).”

Simple polynomial curve fitting described the relationship between porosity and disintegration time as well as dissolution data well for all tested batches.

“Finally, the use of a simple polynomial curve fitting described the relationship between the porosity and the disintegration time as well as dissolution data well for all the tested batches tablets.”

Ibuprofen tablets had relatively shorter disintegration times than indomethacin tablets.

“The relative short disintegration times of the ibuprofen tablets compared to that of the indomethacin tablets (see Fig. 4) partly explains the trend in dissolution rates of ibuprofen and indomethacin observed in Fig. 5.”

Using the Ryshkewitch-Duckworth equation, the averaged fitting parameters for tensile strength versus terahertz porosity across all tablet sets were R-squared of about 0.99 and RMSE of about 0.014 MPa.

“The averaged fitting parameters that were obtained using the Ryshkewitch-Duckworth Equation[49][50][51] of all sets of tablet were R 2 ≈ 0.99 and RMSE ≈ 0.014 MPa.”

• cites [49][50][51]Not checked yet

  Not checked in the free run.

To obtain reliable intrinsic refractive indices, flat-faced tablets were used because they are simpler and more uniform than biconvex ones.

“Flat-faced tablets were used to ensure the accurate determination of the intrinsic refractive index of the formulations given the relatively simple and homogenous nature of flat-faced tablets compared to biconvex tablets.”

For IR tablets, drug release and dissolution cannot occur without disintegration.

“tablet disintegration is a necessary requirement for release and dissolution of the drug from IR tablets”

• cites [22] Markl, 2017, A review of disintegration mechanisms and measurement techniques, Pharm Res sourceNot checked yet

  Not checked in the free run.

Earlier work reported a strong relationship between THz-derived porosity or effective refractive index and dissolution behavior of IR tablets.

“a previous work by Markl et al. 17 has established a strong correlation between the measured terahertz effective refractive index/porosity and the drug dissolution characteristics of IR tablets.”

• cites [17] Markl, 2017, Non-destructive determination of disintegration time and dissolution in immediate release tablets by terahertz transmission measurements, Pharm Res sourceNot checked yet

  Not checked in the free run.

Industry has not commonly adopted porosity measurement as a quality check for IR tablets.

“the measurement of tablet porosity has not been a popular method for checking the quality of IR tablets in the industry.This may be due partly to the relatively time-consuming and destructive nature of existing conventional porosity measurement methods like mercury or helium porosimetry 16,29,30 .”

• AssumptionRests on an assumption: Traditional quality-control tests for tablets are resource-intensive, slow, destructive, and cover only a small fraction of product.

The THz porosity approach was shown to be valid for IR tablets containing ibuprofen or indomethacin, covering different shapes and both debossed and non-debossed forms.

“The validity of the terahertz porosity method was established across a range of immediate release (IR) formulations of ibuprofen and indomethacin tablets of varying geometries as well as with and without debossing.”

For IR tablets, the processes of disintegration and drug release are closely connected.

“In the case of immediate release (IR) tablets, the disintegration and the drug release processes are tightly linked”

• cites [18] 1999Not checked yet

  Not checked in the free run.

The THz porosity method is robust because debossed and non-debossed tablets gave comparable results.

“The promising results obtained for the debossed tablets (Fig. 3 (e) & (f)) in comparison with non-debossed counterparts (Fig. 3 (c) & (d)) demonstrates the robustness of the terahertz porosity measurement method.”

A reason reliable dissolution prediction is hard is that earlier techniques do not directly measure bulk tablet properties like porosity, which control mass transport during disintegration and release.

“This is due to the inability of these methods to directly probe and quantify the bulk physical properties of tablets, e.g.porosity, that directly govern mass transport mechanisms in a tablet during its disintegration and subsequent drug release 16,17 .”

• cites [16] Markl, 2018, Characterisation of pore structures of pharmaceutical tablets: a review, Int J Pharm sourceNot checked yet

  Not checked in the free run.

• cites [17] Markl, 2017, Non-destructive determination of disintegration time and dissolution in immediate release tablets by terahertz transmission measurements, Pharm Res sourceNot checked yet

  Not checked in the free run.

Knowing the intrinsic refractive indices allows THz measurement of porosity in tablets of various shapes made from the same formulations.

“Once the accurate intrinsic refractive indices of the formulations are known, the porosity of batches of tablets with different geometries compressed from these formulations can be measured by the terahertz method.”

THz-TDS in transmission directly measures tablet porosity without chemometric analysis.

“To overcome the above limitations, terahertz time-domain spectroscopy (THz-TDS) has been developed in transmission to directly measure the porosity of tablets [31][32][33] without chemometric analysis.”

• cites [31][32][33]Not checked yet

  Not checked in the free run.

Reliably predicting dissolution profiles with the above methods remains difficult.

“However, the use of the above methods to reliably predict the dissolution profiles is still challenging.”

At very high porosity levels, certain disintegrants do not always follow the expected faster disintegration or dissolution behavior.

“However, this is not always the case for certain types of disintegrants at very high tablet porosity levels (e.g., for rapidly disintegrating or dissolving tablets).”

• cites [26] Bi, 1999, Evaluation of rapidly disintegrating tablets prepared by a direct compression method, Drug Dev Ind Pharm sourceNot checked yet

  Not checked in the free run.

With an acquisition time of 0.12 s, an at-line or on-line terahertz sensor could measure up to 30,000 tablets per hour.

“An acquisition time of 0.12 s means we can realise an atline/on-line terahertz sensor that can measure up to 30,000 tablets per hour.”

The study demonstrated that a fast, non-destructive terahertz porosity measurement method can predict drug release properties, namely disintegration time and dissolution, of pharmaceutical tablets.

“This study demonstrated the robustness of a fast and non-destructive terahertz porosity measurement method that can predict drug release properties (disintegration time and dissolution) of pharmaceutical tablets.”

The THz method still faces challenges because porosity is the only parameter used to predict drug release and dissolution from tablets.

“Despite the non-destructive nature of the THz method, it still faces some challenges given the use of porosity as the only parameter to predict the release and dissolution properties of a drug from tablets.”

This excellent linear correlation demonstrates the robustness of the terahertz approach for tablet porosity measurement even for tablets with high-absorbing APIs, embossing, and different geometries.

“The excellent linear correlation observed between the terahertz porosity and the nominal porosity has manifested the robustness of the terahertz approach for tablet porosity measurement even for tablets containing high absorbing APIs, embossing and of different geometries.”

Swelling of disintegrants such as CCS has been reported to involve gel formation that can substantially lengthen disintegration time.

“The swelling of disintegrant like CCS has been reported to be accompanied by gel formation that can significantly prolong the disintegration time 26 .”

• cites [26] Bi, 1999, Evaluation of rapidly disintegrating tablets prepared by a direct compression method, Drug Dev Ind Pharm sourceNot checked yet

  Not checked in the free run.

The method is suitable for rapidly disintegrating tablets that contain highly soluble APIs.

“Hence this method is suitable for rapidly disintegration tablets containing highly soluble APIs.”

The curvature, lensing effects, and thickness of the tablets have a negligible effect on the measured porosity.

“Based on the excellent results of both flat-faced and biconvex tablets in conjunction with the relatively long Rayleigh range of the used terahertz beam as we have extensively discussed in 34 , we can infer that curvature, lensing effect and thickness of the tablets have negligible impact on the measured porosity.”

• cites [34] Bawuah, 2020, Terahertz-based porosity measurement of pharmaceutical tablets: a tutorial, J Infrared, Millimeter, Terahertz Waves sourceNot checked yet

  Not checked in the free run.

The shorter disintegration times of ibuprofen tablets partly explain the dissolution rate trend between ibuprofen and indomethacin.

“The relative short disintegration times of the ibuprofen tablets compared to that of the indomethacin tablets (see Fig. 4) partly explains the trend in dissolution rates of ibuprofen and indomethacin observed in Fig. 5.”

• AssumptionRests on an assumption: The disintegration rate of a tablet significantly affects dissolution by exposing drug particles to the dissolution medium.

Gel can block pores and thereby slow the rate of liquid uptake.

“The presence of gel can occlude the pores and hence delay the liquid uptake rate.”

Porosity plays a major role in tablet dissolution kinetics.

“Although 17 ibuprofen appears to dissolve faster from the tablets than indomethacin, porosity is again and 18 unsurprisingly seen to play a major role in the tablet dissolution kinetics.”