Applying terahertz technology for nondestructive detection of crack initiation in a film-coated layer on a swelling tablet

Abstract

Here, we describe a nondestructive approach using terahertz wave to detect crack initiation in a film-coated layer on a drug tablet. During scale-up and scale-down of the film coating process, differences in film density and gaps between the film-coated layer and the uncoated tablet were generated due to differences in film coating process parameters, such as the tablet-filling rate in the coating machine, spray pressure, and gas–liquid ratio etc. Tablets using the PEO/PEG formulation were employed as uncoated tablets. We found that heat and humidity caused tablets to swell, thereby breaking the film-coated layer. Using our novel approach with terahertz wave nondestructively detect film surface density (FSD) and interface density differences (IDDs) between the film-coated layer and an uncoated tablet. We also found that a reduced FSD and IDD between the film-coated layer and uncoated tablet increased the risk of crack initiation in the film-coated layer, thereby enabling us to nondestructively predict initiation of cracks in the film-coated layer. Using this method, crack initiation can be nondestructively assessed in swelling tablets after the film coating process without conducting accelerated stability tests, and film coating process parameters during scale-up and scale-down studies can be appropriately established.

1. Introduction

Process analytical technology (PAT) is a system for designing, analyzing, and controlling the manufacture of pharmaceutical compounds through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. The United States Food and Drug Administration (FDA) asserts that PAT can reduce production cycle times via on-, in-, and at-line measurements and controls, thereby preventing rejects, scrapping, and re-processing; facilitating real time release; increasing automation to improve operator safety and reduce human error; improving energy and material use; and increasing capacity and facilitating continuous processing to improve efficiency and manage variability [3].

The International Conference on Harmonization (ICH) has stated that providing flexibility for future process improvement will benefit from developing measurement systems that allow for monitoring of critical attributes or process end-points when describing the development of the manufacturing process [5]. The ICH then goes on to state that collection of process monitoring data during development of the manufacturing process for new pharmaceutical drugs can provide useful information to enhance process understanding [5]. In addition, an effective quality risk management approach can further ensure high quality of the drug (medicinal) product by providing a proactive means to identify and control potential quality issues during development and manufacturing [6]. Further, the ICH requires that pharmaceutical companies plan and execute a system for monitoring process performance and product quality to ensure that control is maintained [7].

The FDA describes PAT as a more advanced technology for quality by design (QbD), accomplishing continuous improvement using timely analysis and control loops to adjust the processing conditions and maintain constant output [4]. A number of publications have reported on the merits of using near-infrared spectroscopy (NIRS) as a nondestructive PAT tool for in-line quality monitoring during wet granulation [8,9,27], the blending process [21,25,33], and at-line quality monitoring of non-coated tablets [1,16,24]. NIRS is also an effective PAT analyzer in estimating product quality, as this method requires no pretreatment of samples and provides speedy detection, low damage to samples, and is nondestructive.

Recently, terahertz technology including both spectroscopy and imaging has also been used in drug research, in capacities such as detecting crystal transition rate, assessing polymorphic content, and in structural analysis of compounds [14,18,26,28–30]. Several authors have described the benefits of using terahertz spectroscopy over NIRS [2,22]. One particularly useful application of terahertz technology as a PAT tool is in end-point detection in the film coating process [23]. Indeed, terahertz spectroscopy is more effective at detecting coating thickness directly, without preparing for calibration models using weight gains, than NIRS. NIRS calibration model detecting end-point of coating is created by using a correlation between NIR absorption and the amount of coating materials. If coating process would like to be stopped at the targeted coating thickness, NIRS is not an adequate PAT tool because NIR absorption relates to the amount of coated materials. Coating thickness often dominates properties of pharmaceutical products more than the amount of coated materials. Also, NIRS is affected by physical properties of analyte. One of the benefits using terahertz wave is the principle of the measurement. Using the index of refraction for analyte is a unique technology compared with other PAT analyzers. Terahertz technology is not affected by physical properties of analyte because the terahertz pulse goes straight in analyte with little diffusion. Terahertz technology also has been used to nondestructively predict dissolution properties for tablets and pellets [10–13]. Additionally, the valuable application studies of terahertz spectroscopy for pharmaceutical compounds and tablets with chemo metrics have also been reported [31,32].

There are tablets using swelling polymers including PEO/PEG formulation [17,19]. Swelling check has been conducted by appearance check visually. Recently, ultra sounds techniques have also been used to monitor swelling of hydrophilic polymer matrix tablets [20].

Here, we explored a novel and a new approach using terahertz technology as a PAT tool to nondestructively predict crack initiation in the film-coated layer of swelling tablets.

2. Materials and methods

2.1. Materials

Opadry red and opadry orange were purchased from Colorcon Inc. (Harleysville, PA, USA). Film-coated tablets prepared by Astellas Pharma. Inc. (Tokyo, Japan) were used for this study. Two batches of uncoated tablets were prepared with a 50-mg difference in total weight between them. In addition, these uncoated tablets contained expandable excipients.

2.2. Manufacture of film-coated tablets

Table 1 summarizes the characteristics of the manufactured uncoated tablets, while Table 2 shows typical manufacture conditions for the film-coated tablets and the rate of crack initiation (RCI) in the high-temperature degradation test. Calculation of RCI was conducted by using 10 tablets for each batch.

$$RCI=\mathrm{The}\mathrm{number}\mathrm{of}\mathrm{cracked}\mathrm{tablets}/10\times 100$$ (1)

Table 1.

Characteristics of manufactured uncoated tablets.

Batch	Uncoated tablet	Diameter (mm)	Thickness (mm)	Weight (mg)
X6	A	9.1	5.4–5.5	341.6
Y9	B		6.0–6.1	391.6

Table 2.

Typical manufacturing conditions and quality of film-coated tablets.

Batch	Uncoated tablet	Coating		Manufacturing scale	Size of spray mist	Rate of crack initiation (%)
		Base	Weight (mg)
X6-1	A	Opadry Red	10.2	Pilot	Standard	0
X6-2		Opadry Red		Pilot	Large	80
X6-3		Opadry Red		Pilot	Small	0
Z6-1		Opadry Red		Commercial	Standard	40
Y9-1	B	Opadry Orange	11.7	Pilot	Standard	0
W9-1		Opadry Orange		Commercial	Standard	40

Six batches of film-coated tablets using different coating materials, production scales, and spray mist diameters were manufactured. After film coating process, tablets were taken from a coating pan and stored in a drying oven (DO-450VC; AS ONE). While no cracks were noted under high-temperature conditions for three of the batches, cracks were observed in the side surface of film-coated tablets in the other three batches, at a ratio of 40–80% of tablets in each affected batch. Images of film-coated tablets stored in the drying oven at 70 °C for 1 h are shown in Fig. 1. Also, high-temperature degradation tests using the drying oven (at 60 °C or 70 °C) were conducted in order to evaluate a crack initiation of film-coated tablets with different FSD and IDDs. After several degradation tests at 70 °C, we reduced the oven temperature from 70 °C to 60 °C, because we found that the milder conditions at 60 °C were believed to be better for detecting differences in sample appearance than those at 70 °C.

Fig. 1.

Film-coated tablets stored in a high-temperature oven (60 min at 70 °C) (a) without a crack and (b) with a crack.

2.3. THz wave measurement (instrumentation and data analysis)

Tablets were subjected to terahertz wave measurement using a TAS7000 (Advantest, Tokyo, Japan). The optical system of the equipment used in the present study was remodeled to enable reflection measurement of tablets. Details of the TAS7000 and element technologies have already been reported [15]. Briefly, an ultrashort light pulse (duration<90 fs) emitted from one of the two ultrashort fiber lasers is incident on the photoconductive switch (PCS) for excitation (Fig. 2). The PCS has a dipole antenna, to which a bias is applied, patterned on a semiconducting substrate with a low-temperature-grown GaAs layer. When the ultrashort light pulse illuminates the gap in the dipole antenna of the PCS, electric current flows in the gap for a fraction of a second, and an electromagnetic pulse is emitted.

Fig. 2.

Block diagram of the terahertz wave measurement system TAS7000 and schematic optical system for reflection measurement of film-coated tablets.

In addition, another PCS of the same structure is used to detect terahertz waves. When an ultrashort light pulse is irradiated from the other ultrashort fiber lasers whenever a terahertz wave enters the field, electric current flows through the antenna for a split second in proportion to the electric field of the terahertz wave. The terahertz wave is then detected based on the presence of the electric current. Accurately controlling the timing for transmitting the ultrashort laser pulses to the respective PCSs, the time domain waveform of terahertz waves can be acquired through detecting the electric field of terahertz waves. In addition, the power spectrum of the frequency domain through a fast Fourier transform (FFT) can be obtained from the time domain waveform, thereby allowing spectrometry to be performed. The measurement frequency range of this system is up to 3 THz and the dynamic range is more than 50 dB.

In the present study, terahertz waves were irradiated onto a predefined point on a film-coated or uncoated tablet (peak of the curved surface of the tablet; Fig. 2). The time domain waveform of the mirror-reflected terahertz wave was then analyzed. A reflected wave was acquired as a reference waveform by conducting this process using a metal mirror instead of a tablet.

An example of time domain terahertz-wave signals reflected back from the metal mirror and a film-coated tablet is shown in Fig. 3. The reference signal e_ref(t) and the measurement signal e_sam(t) denote reflection signals from the metal mirror and film-coated tablet, respectively. Each signal is normalized to the maximum reference signal. The origin of the horizontal axis corresponds to the surfaces of the metal mirror and film-coated tablet. For the film-coated tablet, the positive portion of the horizontal axis shows the time delay containing the information on the internal structure and material properties.

Fig. 3.

Terahertz reference signal. e_ref(t) (green signal) and measurement signal e_sam(t) (blue signal). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

At the origin in Fig. 3, the amplitude of the reference signal e_ref(t) is given by I₀, and the amplitude of the measurement signal e_sam(t) is given by I₁. The reflectance R₁ of a film-coated or uncoated tablet is obtained from the ratio of these amplitudes:

$$R_1=I_1/I_0$$ (2)

When an electromagnetic wave is incident on interfaces (material to be measured) with different refractive indices, the reflectance is obtained using Fresnel's formula. When p-polarized light is incident on the plane, the reflectance R₁ can be expressed as follows:

$$R_1=\frac{n_1\cos \alpha -n_0\cos \beta }{n_1\cos \alpha +n_0\cos \beta }$$ (3)

Here, n₀ is the refractive index (approximately 1.0) of the medium in which the object to be measured is placed, and n₁ is the refractive index of the surface of the object to be measured. α is the incidence angle of the electromagnetic wave on the object to be measured, and β is the diffraction angle of the electromagnetic wave transmitted into the inside of the object to be measured. The reflectance R₁ is known to change depending on the refractive index of the surface of the object to be measured (film-coated or uncoated tablet), which can be regarded as a parameter representing the density of the material. Therefore, we can nondestructively and quantitatively determine the density by measuring the reflection of a tablet using terahertz waves. The reflectance R₁ can also be termed as the “film surface density” (FSD) of the film layer. At an incidence angle of 0°, the FSD can be expressed as follows:

$$FSD=\frac{n_1-n_0}{n_1+n_0}$$ (4)

Furthermore, R₁ of an uncoated tablet was defined as the “uncoated surface density” (USD).

In Fig. 4(a), scaled waveforms are superimposed so that the peak value of the main pulse reference signal e_ref(t) is equal to that of the measured signal e_sam(t). By assuming that the coating material of the film-coated tablet has no dispersion in the terahertz domain, the different waveforms of these signals (Fig. 4b) can be used to selectively extract the reflection signal from the inside of the film-coated tablet. The fall at t₁ in the horizontal axis of Fig. 4(b) is a signal reflected from the boundary between the film-coated layer and the tablet core of a film-coated tablet. Fresnel's formula suggests that the amplitude I₂ at t₁ changes with the refractive index difference (density difference) at the boundary between the film-coated layer and the tablet core. Here, using I₀ obtained by reference measurement, the interface density difference (IDD) is defined as

$$IDD=I_2/I_0$$ (5)

Fig. 4.

(a) Scaled reference terahertz signal (green signal) and measured signal from the tablet (blue signal). (b) Difference between scaled reference and measured signals. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

The polarity of IDD is determined from the relative magnitude of the refractive index n₁ of the film-coated layer and the refractive index n₂ of the tablet core, and is expressed as follows:

$$IDD>0(n_1<n_2)IDD<0(n_1>n_2)$$ (6)

IDD can thus be considered an index to express the sharpness of the boundary between the film-coated layer and the tablet core.

In addition, the time lag Δt₁(=t₁–t₀) in Fig. 4 changes depending on the thickness of the film-coated layer. When the terahertz wave is perpendicularly incident on the film-coated tablet, the film thickness L of the film-coated layer can be expressed by using the speed of light, c as follows:

$$L=\frac{c\mathrm{\Delta }{t}_1}{2n_1}$$ (7)

3. Results and discussion

From each batch of film-coated tablets, 11 samples for the reflection measurement using terahertz waves were chosen for FSD and IDD analysis. At the same time, reflection measurement of three X6 (uncoated tablet A) samples and three Y9 (uncoated tablet B) ones was conducted. Also, USD analysis was conducted for X6 and Y9. Mean values and standard deviations (SD) of FSD and IDD are shown in Table 3. Of interest, the mean value of FSD for the batches of film-coated tablets in which cracks were noted in the film-coated layer (X6-2, Z6-1, W9-1) was smaller than that for the batches of film-coated tablets in which cracks were not noted (X6-1, X6-3, Y9-1). The measurement frequency range of this system is up to 3 THz and the dynamic range is more than 50 dB. Considering the measurement frequency range and the dynamic range of this system, 1% difference of FSD is significant. Additionally, the results of the two-sided, two-sample t-distribution tests using the mean value of the parent population were shown in Table 3. One of the two samples was always from the X6-1 batch, and its significance was verified against the other batches. The significance level was assumed to be 5%. FSD values for batches of film-coated tablets in which cracks were not noted (X6-1, X6-3, Y9-1) were confirmed to be different from those for them of in which cracks were noted in the film-coated layer (X6-2, Z6-1, W9-1) statistically by t-test.

Table 3.

Surface density and interface density difference of the manufactured tablets.

Batch		X6-1	X6-2	X6-3	Z6-1	Y9-1	W9-1	X6	Y9
Manufacturing scale		Pilot	Pilot	Pilot	Commercial	Pilot	Commercial	–	–
Size of spray mist		Standard	Large	Small	Standard	Standard	Standard	–	–
Rate of crack initiation (%)		0	80	0	40	0	40	–	–
FSD and USD (%)	T1	22.58	21.27	21.81	17.92	20.28	19.04	17.60	17.34
	T2	22.25	21.11	21.05	19.00	20.28	19.08	17.73	17.48
	T3	21.41	20.86	20.89	19.35	20.97	20.11	16.85	17.96
	T4	20.74	19.70	21.27	19.11	20.80	19.72	–	–
	T5	21.82	19.92	20.78	21.45	21.91	19.13	–	–
	T6	21.11	20.60	21.82	20.07	20.15	19.12	–	–
	T7	21.94	20.37	21.50	20.86	22.88	19.44	–	–
	T8	20.90	18.24	21.24	20.67	21.51	20.03	–	–
	T9	21.39	20.19	22.04	20.48	21.22	18.27	–	–
	T10	22.41	19.51	22.09	20.96	20.75	18.96	–	–
	T11	22.05	18.25	20.49	22.32	21.56	18.79	–	–
	Mean	21.7	20.0	21.4	20.2	21.1	19.3	17.4	17.6
	SD	0.6	1.1	0.5	1.3	0.8	0.6	0.5	0.3
t-test		–	1.50E−04	1.96E−01	2.15E−03	8.01E−02	4.31E−09	–	–
IDD (%)	T1	−6.27	−6.63	−7.31	−6.21	−7.31	−6.50	–	–
	T2	−7.05	−7.47	−7.73	−6.22	−7.31	−6.93	–	–
	T3	−6.74	−7.38	−7.69	−6.36	−7.24	−6.64	–	–
	T4	−7.04	−6.36	−6.97	−6.23	−7.51	−6.55	–	–
	T5	−6.86	−7.19	−6.75	−6.98	−7.86	−6.70	–	–
	T6	−7.74	−6.49	−6.89	−6.96	−8.01	−6.17	–	–
	T7	−7.07	−7.02	−7.11	−6.62	−8.59	−6.76	–	–
	T8	−6.66	−6.07	−7.66	−6.99	−7.65	−6.71	–	–
	T9	−6.77	−6.69	−7.06	−6.75	−7.43	−6.89	–	–
	T10	−7.88	−6.63	−8.19	−7.13	−7.30	−6.13	–	–
	T11	−7.92	−5.36	−6.69	−7.49	−7.24	−6.48	–	–
	Mean	−7.1	−6.7	−7.3	−6.7	−7.6	−6.6	–	–
	SD	0.5	0.6	0.5	0.4	0.4	0.3	–	–

Different spray mists were created by changing atomizer air volume and airflow pattern.

The batches with small mean FSD included the batch (X6-2) in which the spray mist diameter in the coating process was larger than the standard value and those batches (Z6-1, W9-1) where the scale differed from the standard. As such, we may assume that a relatively large spray mist diameter tends to generate a low-density film-coated layer. From the viewpoint of crack initiation, low FSD suggests relatively little tensile strength in the film-coated layer, and consequently, an increased probability that the layer will be disrupted due to expansion of the tablet core. As such, having a low FSD is believed to be a condition contributing to crack induction in the film-coated layer.

As shown in Table 3, the highest mean USD value for uncoated tablets was 17.6% (Y9), which is more than 1.7% less than the lowest mean value of FSD (19.3%, W9-1). On examining the IDD values, the IDD in the batches of film-coated tablets in which cracks were noted in the film-coated layer was at least 0.4% less than the value in the batch without cracks. On comparing coating processes, the level of IDD was relatively low in the X6-2 batch (−6.7%±0.6%), which had a larger coating mist diameter than the standard value, and the Z6-1 (−6.7%±0.4%) and W9-1 batches (−6.6%±0.3%), where the production scale differed from that for the X6-1 batch (−7.1%±0.5%). Of note, all IDD analysis results were negative because, as shown in the relation of Eq. (5), the FSD of the film-coated layer was higher than the USD of the tablet core in all batches of film-coated tablets. We may observe such a trend of having small absolute values of IDD in any batch where we find cracks in the film-coated layer.

IDD can be viewed as an index representing the interfacial sharpness between the film-coated layer and tablet core. Under the coating processes adopted in this study, both spray mist diameters and production scales varied. As such, depending on the process conditions, different spray mist conditions may have been applied to the uncoated tablet surface during coating, thereby creating different interface conditions between the film-coated layer and tablet core. These varying conditions may thus create a difference in sharpness at the interface between the film-coated layer and tablet core, producing different IDD values for different batches. Ultimately, a higher absolute value of IDD indicates a clearer difference between the coated layer and tablet core. If sharpness between film coated layer and tablet core is unclear, it is difficult for film coated materials to be extended smoothly on swelling tablets. This is a reason why small absolute values of IDD in any batch where we find cracks in the film-coated layer.

3.1. Nondestructive prediction of cracks in the film-coated layer

We then examined techniques for predicting crack initiation in the film-coated layer using the analysis parameters discussed earlier in the manuscript. We confirmed above that FSD and IDD analyzed by terahertz waves tended to be low in batches of film-coated tablets in which a crack occurred in the film-coated layer under high-temperature conditions. This finding therefore suggested that low density of the film-coated layer and indistinctness of the boundary surface between the film-coated layer and tablet core were related to crack initiation in the film-coated layer under high-temperature conditions. Therefore, the index obtained by multiplying the FSD and IDD could potentially be useful in predicting crack initiation in the film-coated layer. The film-coating strength index (FCSI) was therefore defined to verify its relationship with crack initiation as follows:

$$FCSI=|FSD\times IDD|$$ (8)

A smaller FCSI value indicates an elevated risk of crack initiation. Table 4 shows the calculated values of FCSI for the measured film-coated tablets and the results of the two-sided, two-sample t-distribution tests using the mean value of the parent population. These measurements were conducted before degradation tests. One of the two samples was always from the X6-1 batch, and its significance was verified against the other batches. The dispersion ratio of the samples was evaluated by using an F-test and an appropriate t-test method was selected. The significance level was assumed to be 5%.

Table 4.

FCSI values of the batches calculated using Eq. (7) before degradation tests.

	X6-1	X6-2	X6-3	Z6-1	Y9-1	W9-1
T1	141.6	141.0	159.4	111.3	148.2	123.7
T2	156.8	157.6	162.7	118.2	148.2	132.3
T3	144.3	153.9	160.6	123.1	151.9	133.6
T4	146.1	125.4	148.3	119.1	156.1	129.1
T5	149.8	143.3	140.3	149.7	172.1	128.1
T6	163.3	133.7	150.2	139.7	161.4	117.9
T7	155.2	143.0	152.9	138.0	196.6	131.4
T8	139.3	110.7	162.7	144.5	164.7	134.4
T9	144.8	135.0	155.6	138.2	157.6	126.0
T10	176.7	129.3	180.8	149.6	151.5	116.2
T11	174.6	97.8	137.0	167.1	156.2	121.7
Mean	153.9	133.7	155.5	136.2	160.4	126.8
SD	12.9	17.7	12.0	16.8	14.0	6.2
t-test	–	6.2E-03	7.6E-01	1.2E-02	2.7E-01	4.0E-06

Table 4 shows that FCSI was particularly low in the X6-2 batch, which had the largest RCI value of all batches examined; in addition, FCSI was also low in batches Z6-1 and W9-1, in which cracks were noted. The p-value (two-sided probability) of the t distribution test in all the batches with cracks in the film-coated layer is sufficiently smaller than the significance level, suggesting a large statistical difference. However, there should be no statistical difference in the batches without cracks where the p-value is higher than the significance level. Taken together, these results indicate a statistically significant difference in FCSI between batches with and without cracks in the film-coated layer.

RCIs of batches X6-2, Z6-1, and W9-1, which all showed cracks in the film-coated layer, were 80%, 40%, and 40%, respectively, indicating that some tablets in these batches experienced no cracks even under high-temperature conditions. A histogram of FCSIs from Table 4 was compiled to clarify the relationship between FCSI distribution and the RCI of each batch (Fig. 5). FCSIs of the batches with an RCI of 0% are distributed above 130 (Fig. 5a, c, and e), while those with an RCI of >0 are distributed below 130 (Fig. 5b, d, and f). This histogram suggests that the values of FCSI below 130 are due to the film-coated tablets with cracks.

Fig. 5.

Histogram of FCSI for 11 film-coated tablets: (a) batch X6-1, (b) batch X6-2, (c) batch X6-3, (d) batch Z6-1, (e) batch Y9-1 and (f) batch W9-1.

3.2. Verification of correlation between FCSI and the crack initiation

Using film-coated tablets from batch W9-1 with RCI 40%, accelerated degradation tests were conducted to verify the correlation between FCSI values and crack initiation of the film-coated layer. From batch W9-1, the film-coated tablets with the largest and smallest FCSI values were stored in a drying oven (DO-450VC; AS ONE, Osaka, Japan) for 80 min at 70 °C. The appearance of the film-coated tablets was visually inspected by opening the door of the drying oven approximately every 10 min. The open portion of the drying oven is covered with a transparent plastic film to prevent heat from escaping if the door is left open at the time of observation.

Fig. 6 shows the film-coated tablets during and after the accelerated degradation test (80 min). While a crack formed in the film-coated tablets with the lowest FCSI in batch W9-1 at 60 min after starting the test, no cracks were found in the tablets with the highest FCSI. The crack in the film-coated layer is clearly recognizable in the photographs in Fig. 6 taken during the test (0–80 min). This result shows that crack appearance was properly predicted based solely on FCSI values in the batches of film-coated tablets—even in batches such as W9-1, which included tablets with and without cracks in accelerated degradation tests. For pharmaceutical companies, tablets must be developed while taking into account degradation risks under a range of conditions. If appropriate nondestructive tools such as our novel tool described here cannot be used, such risks will have to be evaluated in degradation tests, which are costly in terms of development time and financial strain are increased. Our case studies conducted in this paper may be a special example, because we used the unique formulation with swelling materials in non-coated tablets. However, there are lots of merits for terahertz waves used for analyses of pharmaceutical products. One of them is to analyze a coated thickness with a special measurement principle. Our case studies are also one of the good examples using terahertz waves for analyses of pharmaceutical products.

Fig. 6.

Appearance of film-coated tablets in batch W9-1 during and after degradation test (80 min at 70 °C).

3.3. Verification of accuracy of using FCSI in nondestructive prediction of crack initiation

Three groups of eight tablets each with different FCSI values were selected from different batches. The first group was arranged to have relatively small FCSI values, ranging from 118 to 128, the second group to have middle FCSI values, ranging from 134 to 148, and the third group to have large FCSI values, ranging from 158 to 163. The three groups were stored in a drying oven (DO-450VC; AS ONE) for 80 min at 60 °C (reduced from 70 °C because milder conditions were believed to be better for detecting differences in sample appearance).

Samples used in the present studies and the results of crack initiation after degradation tests are listed in Table 5. In addition, Fig. 7 shows the relationship between FCSI and crack initiation. Both highlight the good correlation between FCSI values and crack initiation. Tablets with relatively small FCSI exhibited a dramatically increased ratio of crack initiation compared with tablets with relatively large FCSI. These results support the notion of using FCSI for nondestructive prediction of crack initiation. Figs. 8 and 9 show the film-coated tablets during and after the accelerated degradation test (80 min).

Table 5.

Crack initiation results during degradation tests (80 min at 60 °C).

Group	Sample name	FCSI	Results		Ratio (%)
			Crack initiation	Time (min)
Small FCSI	Z6-1_02	118	Yes	20	75
	Z6-1_05	119	Yes	20
	W9-1_15	122	No	–
	Z6-1_03	123	Yes	20
	W9-1_02	124	Yes	20
	X6-2_07	125	No	–
	W9-1_13	126	Yes	20
	W9-1_06	128	Yes	30
Middle FCSI	W9-1_11	134	Yes	20	25
	Z6-1_07	140	Yes	30
	X6-3_07	140	No	–
	X6-1_02	142	No	–
	X6-1_04	144	No	–
	X6-1_11	145	No	–
	X6-1_05	146	No	–
	X6-3_06	148	No	–
Large FCSI	Y9-1_12	158	No	–	0
	X6-3_01	159	No	–
	X6-3_04	161	No	–
	X6-3_11	163	No	–
	X6-3_02	163	No	–
	X6-1_07	163	No	–
	Y9-1_11	165	No	–
	Z6-1_15	167	No	–

Fig. 7.

Relationship between FCSI values and crack initiation.

Fig. 8.

Crack initiation results during degradation tests for film-coated tablets with different FCSI values (80 min at 60 °C).

Fig. 9.

Crack initiation results after degradation tests for film-coated tablets with different FCSI values (80 min at 60 °C).

4. Conclusion

This novel study reported a new nondestructive technique using terahertz waves to analyze the coating characteristics of drug tablets. Using such a method, the structure and physical characteristics, which are typically difficult to analyze, can be analyzed in the depth dimension of the tablet. We demonstrated our ability to determine the density of the film-coated layer over the tablet core, which has thermally expansive characteristics, as well as the information on the interface between the film-coated layer and the tablet core. In addition, FCSI was newly defined using FSD and IDD values obtained via nondestructive measurement of terahertz waves and presented as a promising index for determining risk of crack initiation in film-coated tablets. Applying these analytical methods using terahertz waves to process development and scale-up and scale-down experiments, which will become increasingly complex in the future, is expected to substantially improve product quality and development efficiency. Effective use of our novel approach will reduce development time and financial cost in terms of effectively determining film coating process parameters without degradation tests. In this paper, we demonstrated nondestructive prediction of cracks in the film-coated layer on a certain swelling tablet. By putting more evaluation with some combination of film-coating materials, swelling tablets and process parameters based on the design of experiments into execution, a typical range of FCSI values from a single batch can be provided for a representative sample of a batch that will crack and other that will not crack. Additional case studies using FSD, IDD and FSCI will be necessary for further discussions about availability of this technology to other tablets.