The 23-year-old center back excelled for the Spanish side last season and is now set to complete a move to White Hart Lane.
Spurs had been considering an offer for the 23-year-old after he was voted the Spanish club’s player of the season in 2013-14, and the teams are now on the verge of completing a deal.
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Marcelino "expects" Musacchio to make the switch to White Hart Lane, despite how difficult he sees the task of finding a replacement.
"It's a situation with three parties: the player, the buyer and the club in the middle and, as I have said many times, if the club sell an important player it's because the right conditions to do so have been met," he said. "Things will change quite a lot [for this team]. The quality and level of [Musacchio] will make it difficult to find a replacement.
"It's always more complicated to adapt the team to a new defender than to a forward or midfielder [and] it's not easy, at this level, to find a new defender. It won't be easy [to replace him] but the solution, for better or worse, will be found soon."
The coach lamented that, having already wanted to bring in another center back this summer, he would now have to find two.
"Mateo is a very important player for Villarreal," he added. "He's an excellent player and will be a difficult loss to cover, especially as he plays in a tough position to reinforce."